18 th meeting of fda tse advisory committee: 31 october 2005 summary fda blood products advisory...

18th Meeting of FDA TSE Advisory Committee:

31 October 2005Summary

FDA Blood Products Advisory Committee85th Meeting

03 November 2005Holiday Inn

Gaithersburg MD

David M. Asher, MD<[email protected]>

Laboratory of Bacterial, Parasitic and Unconventional Agents

Division of Emerging & Transfusion-Transmitted Diseases

Office of Blood Research & ReviewCenter for Biologics Evaluation & Research

US Food & Drug Administration

18th FDA TSEAC Agenda

1. BSE worldwide and USA: USDA update

2. TSE decontamination of surgical devices: CDRH update

3. CBER decisional issue 1. Advice on further development of FDA risk assessment for vCJD and plasma-derived factor VIII

4. CBER decisional issue 2. Validation criteria and possible label claims for devices to remove TSE infectivity from blood components

Recipients surviving >3yrs post transfusion of blood components from vCJD/CJD Donors

(using data from UK TMER and US ARC look-back studies,S. Anderson, FDA TSEAC 14 Oct 2004)

Fisher's Exact Test comparing rates of infection after transfusions from vCJD and CJD donors suggests a statistically significant difference between the two groups (1.2% likelihood that the difference occurred by chance). Risk of transfusion-transmitted vCJD >> sporadic CJD

InfectionNo

Infection

CJD 0 116

vCJD 2 13

vCJD : Non-UK = 27cases(October 2005 UK =158) from R. Knight/CJD SU Edinburgh

FRANCE 15

ITALY 1

NETHERLANDS 1

PORTUGAL 1

SPAIN1

REPUBLIC of IRELAND 2

REPUBLIC of IRELAND 2 USA 1 CANADA 1 JAPAN1

SAUDI ARABIA (source uncertain) 1

Probably acquired in UK Probably non-UK

Donor travel history UK, FR, EuropeAdjustments for duration & year traveled, donor age Screening questionnaire

Plasma pool sizeQuantity of vCJD agent in poolReduction of vCJD agent during manufacture

Percent contaminated vialsAmount vCJD agent per FVIII vialAnnual dose Factor VIII

Module 1vCJD

Prevalence in UK

Module 2vCJD

Prevalence in US Donors

Module 3FVIII

Processing

Module 4Utilization of FVIII

INPUT MODULE OUTPUT

Number US vCJD donorsNumber vCJD donors post-screeningTotal number vCJD donations

Percentage plasma pools / vials with vCJD agentQuantity vCJD agent per FVIII vial

Annual exposure of FVIII recipients to vCJD agent

Estimate of vCJD prevalence in United Kingdom

UK surveillance dataPredictive modeling based on UK vCJD cases

Critical elements of vCJD risk assessment:

Prevalence of vCJD in US Plasma

UK vCJD prevalence US donor travel history Time of travel relative to UK BSE prevalence Travel: Source Plasma vs recovered plasma

donors Risk reduction by donor deferral Effectiveness of donor deferral Residual risk: non-deferred (short-duration)

travelers

Module 1 Prevalence of vCJD in United

Kingdom

Proposed Modeling Approaches

Two sources of UK vCJD prevalence data:

1. Predictive models based on UK vCJD cases2. Surveillance data based on examination of

appendix samples

Problem:Disparity ~ 10 to 100 fold between approaches

Module 1Prevalence of vCJD in UK

Predictive models based on observed cases of vCJD and “back calculation”

method______________________________________________

(1) Ghani et al 2003 vCJD estimated median 100 cases (10

to 2,600 - 95% CI) Median 1 in 500,000

(2) Boelle et al 2003 vCJD UK estimated cases: 183 to 304

(3) Llewelyn et al 2004 vCJD UK est 1 in 15,000 to 1 in 30,000

or 1,000-2,000 infections

Unique Pathology of vCJD (Chazot G & al. Lancet 1996;347:1181. Will RG & al. Lancet

1996:347:921-5. Hill AF & al. Lancet 1999;353:183-9)

Module 1 Prevalence of vCJD in UK

Empirical appendix surveillance data (Hilton et al. 2004)

3 PrPres-positive samples in 12,674 samples tested ~ mean of 1 positive in 4,225 individuals

(mostly 20- to 30-yr-old patients)Approximately 13,000 vCJD infected UK

individuals in UKData should be further age-adjusted using

reported UK vCJD case age profileDoes not consider infected persons before

appendix becomes positive for PrPres (e.g., last transfusion-transmitted infection in a PRNP-codon-129 met/val person)

Issue 1. Advice on Assumptions for vCJD

FVIII Risk Assessment

UK Prevalence: Use empirical prevalence value based on UK PrPres tissue survey allowing for a pre-clinical/sub-clinical infectious state in donors of all PRNP-codon-129 genotypes



Screening sensitivity for vCJD risk: Advised against using estimates from analogous donor screening situations (showing 90-99% sensitivity of screening) and recommended instead 85% most likely

Source Plasma donor information: Encouraged obtaining survey data for travel by apheresis donors rather than extrapolating from a travel survey for donors of Whole Blood

Levels of vCJD infectivity in human plasmaWhat infectivity range (in ID50/ml) should FDA select for human blood/plasma based on studies in animals?

During what part of the incubation period?

FDA proposed a triangular distribution:

Minimum = 0.1 Most likely = 10 Maximum = 310

FDA proposed assuming infectivity to be potentially present in blood throughout the entire incubation period.

From Dr RG Rohwer, Baltimore VAH

InfectedExperimental TSEs: infectivity in blood

|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|| | | | | | | | | | | | | 1 8 16 27 41 51 60 70 80 90 100 120

|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|_0 1 2 3 4 5 6 7 8 9 10 15 20 25 30 35 __|___|___|___|___|___| 42

Weeks Clinical disease

? ?

Uninfected

Days Clinical disease

scrapie in mouse

scrapie in hamster

Eklund/5x107im/30 ul blood clot ic30 ul serum ic2 exp. same result

|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|0 5 10 20 30 40 50 120

Days Clinical disease

scrapie in hamsterDiringer/ 106 ip200 ul blood equiv ic

Cassacia/ 106 ip200 ul blood equiv ic

(214)(151) (151) (186) (191)

(108)(116) (114) (113) (128) (124) (131) (121) (132) (138)

Numbers in parentheses are mean incubation times.

file: Viremia6.pptRobert G. Rohwer, Ph.D.

|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|0 1 2 3 4 5 6 7 8 9 10 15 20 25

CJD in guinea pigManuelidis/ic inoc .1ml clinical/0.1ml buffy coat ic, ip, sc, im

|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___0 1 2 3 4 5 6 7 8 9 10 15

Clinical diseaseWeeks

GSS (fCJD) in mouseKuroda/3x104ic inoc30 ul buffy coat ic &100 ul serum ip/ 100ul rc ip

(281) (213) (156) (142)

Weeks Clinical disease

(443) (463)

(429)(308)(448) (504)(379)

(396)(210)(343)

(184)(307)

(147)

(447)

Infectivity in blood of terminally ill mice inoculated with mouse-adapted

GSS (Fu-1) agent(Brown P et al. Transfusion 1999;39:1169-78)

Infectivity in ic IU/ml

Expt 1 Expt 2

Pool 1

Expt 2

Pool 2

Buffy coat 44 NT 106

Plasma 10 34 22

Titers of scrapie-infected hamster blood

from clinically ill animalsIn

fect

iou

s D

oses

/ml

Titer of TSE Infectivity in Blood of Clinically Affected Animals

ID/m

l

0

5

10

15

20

25

Infe

ctio

us

Dos

es/m

l

Splenectomies

Individual

Pools

meanmedian


Titer in ID/ml of Preclinical Hamster Blood

Days after Inoculation

0 20 40 60 80 100 120 140 160

Infe

cti

ou

s D

os

es

/ml

0

1

2

3

4

5

6

7

Cli

nic

al

Dis

ea

se

Infe

cti

ou

s D

os

e/U

nit

450

2700

90

2250

1800

1350

900

3150

0




Infectivity level: Agreed that—based on rodent data—10 ID50/ml blood most likely and minimum of 0.1 ID50 prudent, but offered mixed advice on upper level (100 to 1000 ID50 mentioned)

Duration of infectivity in blood relative to incubation period: Agreed compromise advice estimating infectivity in last 50% of incubation period, modified if shown to be a critical parameter in sensitivity analysis



Pool size: Agreed with FDA-proposed “bimodal” distribution with pools of 20,000 and 60,000 donations considered most likely

Clearance of TSE infectivity by manufacturing processes: Agreed with FDA proposal to use three different ranges for various products

Issue 1. Plasma fractionation:FDA proposes 3 ranges of estimated vCJD infectivity

clearance by manufacturing Range of reduction

(log10)Process

Likely minimum

2-3 Single step with moderate clearance

Mid-range 4-6 Single step with higher clearance or Multiple additive steps

Likely maximum

7-9 Multiple additive steps


FVIII Risk Assessment Clinical use: Agreed with FDA that CDC

databases for FVIII use (1993-98 survey of all HA pts in 6 states and Universal Data Collection Program [UCD]) were best available (but not enough—especially for von Willebrand’s disease)

Additional information needed: Agreed with FDA proposal to extrapolate from existing data to estimate use by year and use patient-based medical record data if needed to resolve inconsistencies


FVIII Risk Assessment Cumulative risk from repeated exposures to

“sub-infectious” doses: Agreed with FDA that experimental studies showing infection following frequent exposures of rodents to amounts of infectivity not infectious by single exposures or repeated at long intervals are a concern

Risk per annum: Agreed with FDA proposal to estimate vCJD risk per annum rather than per dose (but did not advise other modification to the risk model)



Special concern: risk communicationRisk of transmission by plasma

derivatives is theoretical. (Even in UK, no case of vCJD has been recognized in a recipient of a plasma derivative.)

Especially difficult to communicate highly uncertain theoretical risks

Notification might cause adverse effects Patient anxiety Health care provider anxiety Other

Participation of patient groups helpful

TSEAC Decisional Issue 2.Validation criteria and possible

label claims for devices to remove TSE infectivity

from blood components UK regulatory authorities plan an

independent evaluation of CE-marked blood filters purported to reduce TSE infectivity: Expect minimal 3 log10 reduction of spiked

infectivity (demo by Western blot and bioassay) at ambient temp and 4oC

Component (RBC) must maintain functionality at expiry by usual tests

Seek “surrogate” markers suitable for QA Three manufacturers described 3

promising devices for clearing TSE agents (one CE-marked)



from blood components TSEAC suggested modifications to FDA’s

proposed criteria: 3 log10 reduction of spiked infectivity

(demonstrated by Western blot and bioassay)

Remove all detectable infectivity from endogenously infected animal blood

2 animal models and 2 strains of TSE agent 1 agent strain derived from cow with BSE

or human with vCJD (rodent-adapted) Filtered blood components should maintain

functionality at expiry by usual tests



from blood components TSEAC suggested modifications to

FDA’s proposed criteria for validation (continued): Desirable to demonstrate that device

removes all detectable endogenous TSE infectivity from whole units of blood of large animals (sheep scrapie/BSE; ?? primates—not yet available)

Since bioassays for residual infectivity by transfusing of animals of the same species, while ideal, are generally not feasible, may test in susceptible transgenic mice (although sensitivity relative to large animals not known)



from blood components TSEAC suggested modifications to FDA’s

proposed criteria for validation (continued): While reproducibility of results at

separate study sites is desirable, it may be difficult to arrange for two labs with required equipment and TSE expertise

Study should be large enough for statistical validity

Studies described might support label claims for reduction of TSE infectivity (small animal models), ?? prevention of transfusion-transmitted TSE (only after large animal study)

18 th meeting of fda tse advisory committee: 31 october 2005 summary fda blood products advisory...

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