Maria Rios, Ph.D.CBER/FDA

Blood Products Advisory Committee May 1st, 2008

2007 WNV Epidemiology &

FDA’s Recommendations on the Use of NAT to Reduce the Risk of Transmission of WNV in

Whole Blood and Blood Components for Transfusion and Human Cells, Tissues, and

Cellular and Tissue-Based Products (HCT/Ps)

Outline

Update on the 2007 season Human cases Animal cases including sentinel chickens Mosquito pools Geographical distribution

Draft Guidance on Blood Donor Screening for Infection with WNV Screening test platform

MP-NAT ID-NAT

Additional Testing Donor Counseling

WNV Update for 2007

47 states, DC & PR43 states

USGS and/or State Dept report as WNV positive: 3,628 animal cases8,625 mosquito pools

CDC: 3,623 human cases:1,213 (33%) WNV ND2,347 (65%) WNF (milder) 63 (2%) unspecified

with a total of 124 deaths

2007

Activity in 47 states, DC & PR

Human cases in 43 states

WNV in the U.S. Human cases from 1999 to 2007

64

72

9

284 264

100119 177 124

1,294 1,459 1,2131,1422,8662,942

1959

9,862

2,539 3,000 4,269 3,6234,156

66

2162

9,600

2,8508,850

181,950218,850194,100171,300429,900

441,300

428,189515,027456,782403,126

3,1509,300 9,900

1,038,526 1,011,698

1.0E+00

1.0E+01

1.0E+02

1.0E+03

1.0E+04

1.0E+05

1.0E+06

1.0E+07

1999 2000 2001 2002 2003 2004 2005 2006 2007Fatality (n = 1,086) WNV ND (n = 11,058)

Cases of Disease (27,598) Estimated infections (1:150 ND, n = 1.7M)

Estimated infections (1:353 ND, n = 3.9M)

WNV Activity in the US

April 20084 Human cases TN (1 in Jan), AZ (1 Mar),

MS (2 Mar, Apr)

1 horse (AL)

12 Dead Birds CA (11), SC (1)

10 Mosquito Pools CA (9), FL (1)

4 Sentinel Chickens FL (2), CA (2)

WNV infection is Notifiable to the CDC

Endemic (peak spring/fall)

Since 2002 yearly:

>1,000 WNV ND

≥ 100 fatalities

Since 2005, onset of WNV clinical cases have been reported to the CDC from Jan to Dec

WNV Blood Screening in the U.S.

From 2003 to 2007 resulted in: Interdiction of ~2,600 WNV NAT-reactive units Prevention of ~2,600 to 7,800 potential transmissions

by transfusion

*All seronegative for WNV; + Lack of f/up, sample, recipient loss‡ Negative in MP-NAT and positive on ID-NAT (low viremia)

Transmission by Transfusion Year 2002 2003 2004 2005 2006 2007

NAT-Reactive Units N/A >1,000 224 417 441 511

TT Confirmed* (n=32) 23 6 ‡ 1 ‡ 0 2 ‡ 0

TT Inconclusive+ (n= 26) 19 6 1 0 0 0

Current Testing AlgorithmTest individually each specimen

included in the pool

If suitable:Released for transfusion

MP-NAT

NAT NR

NAT R

Unit (s) discard; Donor deferred for 120 days

Additional tests performed for counseling purposes

ID-NAT NR

ID-NAT R

Repeat NAT using same or alternate NAT assay

of ≥ sensitivity

Ab to WNVNote: Ab cross-reactivity among Flaviviruses

PPV 98% Sensitivity 98%

Algorithm for Additional Testing of Index Donation Specimen Prior to Donor Counseling

ID-NAT Reactive

Repeat NAT using same or alternate NAT assay of

≥ sensitivity

Ab to WNV

Rep ID-NAT R

Positive

Present

PositiveRep ID-NAT NR

Absent

False Positive or TN

2% TP on Follow up

≤ 10% of IRRep NAT NR

TP on Ab

Issues Regarding Testing

2003: 6 cases of TT-WNV after MP-NAT

MP-NAT detects 75% of WNV infected units (25% undetected)

2004: ID-NAT used in high WNV activity regions

ID-NAT implementation criteria: 1 in 1000 donations reactive or 2 MP-NAT positives in a week, whichever comes first

Since selective ID-NAT: Three (3) confirmed cases of WNV transmission by transfusion (1 in 2004 and 2 in 2006)

Issues Regarding Testing

In April 2007, the following considerations were presented to the BPAC

Uniform criteria to initiate ID-NAT is desirable

Fully automated NAT system licensed

Paucity of data to define uniform criteria

AABB voluntary recommendation: Bulletin #07-02

whether blood establishments should define and validate criteria to trigger ID-NAT and to revert back to MP-NAT

2007 ARC studies on suitability of ID-NAT implementation criteria (SL Stramer, 2008)

Results showed that ID-NAT was required to detect:

148/540 (27%) in 2003-2004

44/154 (29%) in 2005

76/212 (36%) in 2006 (in some cases early implementation based on 2 ID-PVD)

65/147 (44%) 2007 ARC evaluated criteria for ID-NAT implementation

ID-NAT Detected 42 Confirmed WNV Positive Donations in Validation Studies (SL Stramer, 2008)

Trigger criteria 1 PVD** 2 PVD 2 PVD & 1:1000

Yield

Incremental Yield

42* 31 5

11 26

37

**12 /42 (29%) were IgG only

20Yield minus IgG (FP?)

Incremental Yield 10 15

25

30

New data show that the previous criteria for ID-NAT implementation are inadequate

6.2-fold increase

8.4-fold increase

4-fold increase

6-fold increase

*Presumed viremic donor defined as ID-NAT with S/CO ≥ 17 or repeat reactive ID-NAT

5

(100%) (74%) (12%)

(88%)

(100%) (18%)

(83%)

(67%)

Draft WNV NAT Guidance for Industry

Draft Guidance published on April 28, 2008 for comment purposes only

90-day comment period closing in July 27, 2008

Recommendations on Testing Screen for WNV should be performed year-round

using a licensed NAT on donor samples of whole blood and blood components intended for transfusion.

Either MP-NAT or ID-NAT may be used for WNV screening.

ID-NAT should replace MP-NAT during high WNV activity in your region (using a previously defined geographic area).

Screening Algorithm for Blood Donations

ID-NAT reactive unit (s)

If suitable, release unit for transfusion

If suitable, release unit(s) for transfusion

Using a licensed MP-NAT for WNV

Using a licensed ID-NAT for WNV

ID-NAT non-

reactive

MP-NAT non-reactive MP-NAT reactive

ID-NAT non-reactive

unit (s)Test each specimen in the pool by ID-NAT

Discard unit (s).Defer donor (s) for 120 days.Retrieve in-date products from prior collections dating back 120 days.

Initiate WNV ID-NAT for that region

Algorithm for ID-NAT Implementation

ONE ID-NAT reactive unit

MP-NAT reactive Test each specimen in the pool by ID-NAT

Discard unit (s); Defer donor (s); Retrieve in-date

products

Initiate ID-NAT for all collections from that

region in 24 hours

If >24 hours of collection: consider performing retrospective ID-NAT testing of retention samples from collections within that time period

If blood establishments wish to revert back to MP-NAT, they may do so when the high WNV activity in the defined geographic area has subsided (e.g., minimum of 7 days has passed without a single WNV ID-NAT reactive donation)

* If NAT for all JE viruses used, we encourage WNV discriminatory prior to counseling ª Cross-reactivity among different Flaviviruses.

ID-NAT reactive unit (s)

Perform additional testing on index donation specimen as follows:1. Repeat ID-NAT using the same assay or an alternate NAT* of ≥ sensitivity

2. Test for WNV-antibodies (WNV-Ab) using a cleared Ab assay

ID-NAT reactive & WNV-Ab either

Pos or Neg

ID-NAT non-reactive &

WNV-Ab Positiveª

ID-NAT non-reactive & WNV-Ab Negative

Notify of deferral & counsel the donor as testing Positive

for WNV infection

Notify of deferral & counsel the donor as inconclusive for WNV infection.Encourage donor return after 30 days for follow-up testing by ID-NAT and WNV-Ab.

Additional Testing Algorithm

Recommendations Regarding Labeling

Container label and instruction circular to reflect results of WNV NAT, consistent with labeling for other infectious disease markers

“A Licensed Nucleic Acid Test (NAT) for West Nile Virus (WNV) RNA has been performed and found to be non-reactive.”

WNV reactive unit not to be shipped or used except as provided in FDA approved programs and/or research or autologous use only, and such units be labeled with appropriate warnings