FDABlood Products Advisory Committee Meeting

03 August 2011Gaithersburg MD

Summary of Transmissible Spongiform Advisory Committee Meeting

01 August 2011

IssueDonor Deferral/Ineligibility for Time Spent in Saudi Arabia to

Reduce Risk of vCJD Transmitted by Blood and Blood Products and by Human Cells, Tissues and Cellular and

Tissue-Based Products (HCT/Ps)

David M. Asher<david.asher@fda.hhs.gov>

Laboratory of Bacterial & TSE AgentsDivision of Emerging & Transfusion-Transmitted Diseases

Office of Blood Research & ReviewCenter for Biologics Evaluation & Research

US Food & Drug Administration

2

AcknowledgementsCBER

Steven Anderson OBE Bryan Emery OM Jay Epstein OBRR Joe Giglio OBRR Melissa Greenwald OCTGT Luisa Gregori OBRR Ginette Michaud OBRR Pedro Piccardo OBRR Martin Ruta OBRR Jennifer Scharpf OBRR Alan Williams OBRR Hong Yang OBE

Judith Badoo OD Joan Blair OD Diane Maloney OD

Other FDA Sousan Altae OC OIP Layla Batarseh OC OIP Burt Pritchett CVM

TSEAC Frank Rentas DoD Mo Salmon CO State U

Other Robert Will UK CJDSU Michael Coulthart HPA Canada Lawrence Schonberger CDC David Lincoln DoD

Kingdom of Saudi Arabia Food and Drug Authority

3

FDA seeks advice from TSEAC on whether, based on three cases of vCJD in individuals likely to have been infected with the BSE agent in Saudi Arabia, to modify current vCJD-related safety recommendations deferring certain blood and plasma donors or finding certain donors of HCT/Ps ineligible to

donate

for time spent in Saudi Arabia.

Issue for TSEAC

4

vCJD and blood safety

Variant CJD: a human infection with BSE agent (= a “zoonosis”)

Most vCJD infections food-borne Five vCJD infections in UK attributed to blood

products Only one risk-reduction strategy available for blood

components and HCT/Ps: reduce number of donors exposed to BSE agent = geographic donor deferral/ineligibility

Donor testing not yet available Reliable infectivity removal techniques not yet

available (except for plasma derivatives)

5

vCJD and blood safety (2)

Geographic donor deferrals reduce risk but non-specific, inefficient

Donor deferral recommendations not fully effective, not completely consistent

When persons in new countries are recognized to pose a potential vCJD risk, FDA believes it prudent to consider modifying FDA geographic BSE-related recommendations for suitability/eligibility.

6

pdFVIII case

0

5000

10000

15000

20000

25000

30000

35000

40000

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

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2001

2002

2003

2004

2005

2006

2007

2008

2009

BS

E d

eath

s

0

5

10

15

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30

vCJD

dea

ths

Feedban

4 transfusion infections

12/03 7/04 2/06 1/07 2/09

BSE vCJD

BSE and vCJD deaths in UK

7

Estimated incubation periods of vCJD

Food-borne vCJD• Estimated median of 12-13 yr for cases to datein persons with PRNP 129-MM genotype (~ 40% of normal UK

population). • Predicted median ?? 32 yr in persons with genotypes MV (~ 50% UK) and VV (~ 10% UK).Small numbers of cases predicted up to ? > 40 yr after exposure

Transfusion-transmitted vCJD– 1st case 6.3 yr– 2nd case > 5 yr (PrPTSE-pos lymphoid

tissues)– 3rd case 7.8 yr– 4th case 8.5 yr (same donor as 3rd case)

Plasma-derivative associated case– ? 11 yr

Transfusion look-back studies:recipients surviving > 5 yr post

transfusion of labile blood components from vCJD/sporadic CJD donors

----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

All transfusion-transmitted vCJD infections reported to date were in UK recipients of non-

leukoreduced RBC(cf. look-back studies: UK TMER; US ARC)

Conclusion: Transfusion-transmitted vCJD definite; transfusion-transmitted sporadic CJD not detected

Disease (or

infection)

NoDisease

vCJD 4 29

CJD 0 144§

9

How long before onset of clinical vCJD

is blood infectious? Intervals between blood donations and onset of vCJD case or

infection for 3 implicated UK donors

to 4 infected recipients of non-leukoreduced packed RBC:

1.4, 1.5, 1.7, 3.5 years

Conclusion:During the last 3.5 years of incubation period, blood of

[some] clinically healthy PRNP-codon-129-MM donors who later developed vCJD is already infectious.

10

vCJD attributed to infection in Saudi Arabia

3 vCJD cases in long-time residents of Saudi Arabia

All had common vCJD PRNP-129 genotype (MM)

No history of transfusion (2 had surgery)

Presumably food-borne infection

Dates of residence in Saudi Arabia for all 3 cases encompass plausible vCJD food-borne incubation periods.

Other countries less likely places where infection might have acquired, though not impossible

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3 vCJD cases from the Kingdom of Saudi Arabia (KSA)

Case 1 Case 2 Case 3

Birth yr, place (citizenship)

1970KSA

(KSA)

1983KSA

(Egypt)

1986KSA

(Bangladesh)

Early years in KSA

27 16 12 (1986-99)

Other residences USA 1 yr USA Dubai (UAE), Bangladesh, USA,

CanadaTravel UK, France UK UK, Europe

Age at onset 33 23 23Residence at Dx KSA USA Canada

Dx brain bx adenoid/brain bx tonsil bx

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vCJD resembles other forms of CJD but is unique.

0

50

100

1stQtr

3rdQtr

East

West

North

normal brain sCJD cortical spongiform change

vCJD florid plaque

vCJD lymphoid PrP

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vCJD attributed to infection in Saudi Arabia (2)

No vCJD case has been convincingly attributed to residence in any other country of the region.

US (CDC) and Canadian (HPA/Health Canada ) authorities concluded that vCJD was most likely acquired in Saudi Arabia.

Before they became clinically ill, all 3 Saudi-associated vCJD cases would have been considered suitable/eligible to donate blood, plasma and HCT/Ps per current FDA recommendations.

Three UK-associated cases in Dx in N America would have been deferred/ineligible.

14

UK probably exported to Saudi Arabia products potentially contaminated with the BSE agent during the generally-accepted UK BSE-highest-risk period (1980-1996).─ Live cattle─ Beef products─Meat-and-bone meal (MBM)

Saudi Arabia has not recognized BSE in native cattle.

BSE has been recognized rarely in two other countries in the Middle East.─Oman: 2 bovines imported from UK in 1989─ Israel: 1 native bovine in 2002

Estimating possible risk of dietary exposureto BSE agent in Saudi Arabia

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UK exports to other countries of the region 1980-1996 Exports to the region from other BSE countries Cross border trade in the region Risk that undetected indigenous BSE was established

in bovines and (theoretically) in other ruminants in Saudi Arabia from

Rendering practices and feeding of MBM to ruminants

Estimating possible risk of dietary exposureto BSE agent in Saudi Arabia (2)

_________________________________________________

Uncertain but possibly relevant BSE risks

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vCJD cases per estimated population 2011

CountryvCJDcasesa

Estimated population 2011b Crude ratec

UK 175 62,688,000 2.8 x 10-6

Ireland 2 4,671,000 4.3 x 10-7

France 24 65,103,000 3.7 x 10-7

Portugal 2 10,760,000 1.9 x 10-7

Netherlands 3 16,847,000 1.8 x 10-7

Spain 5 46,755,000 1.1 x 10-7

Saudi Arabia 3 26,132,000 1.1 x 10-7

Italy 2 61,017,000 3.3 x 10-8

Japan 1 126,476,000 7.9 x 10-9

[a] Cases resident in UK 6 mo attributed to UK. [b] US Census Bureau estimates mid-2011[c] Not corrected for population age distribution or efficiency of case recognition/reporting.

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UK Exports of Bovine Carcass Meat 1978 – 1998 (M. Ricketts/WHO Presentation to TSEAC 17 Jan 2002http://www.fda.gov/OHRMS/DOCKETS/ac/02/slides/3834s1.htm)

No data

0 - < 5

5 - < 10

10 - < 20

20 - < 100

100 - < 1.000

1.000 - < 10.000

> 10.000

Legend:

(in tonnes)

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Total UK Exports of MBM 1988 – 1993(M. Ricketts/WHO Presentation to TSEAC 17 Jan 2002http://www.fda.gov/OHRMS/DOCKETS/ac/02/slides/3834s1.htm)

No data

0 - < 5

5 - < 10

10 - < 20

20 - < 100

100 - < 1.000

1.000 - < 10.000

> 10.000

Legend:

(in tonnes)

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Estimating possible risk of dietary exposureto BSE agent in Saudi Arabia.

_____________

Meat imports from the UK (1980–1996)

Sanchez-Juan P et al. Source of variant Creutzfeldt-Jakob disease outside United Kingdom. Emerg Infect Dis 2007;13:1166-9

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FDA Considerations Regarding Saudi vCJD Cases

Crude rate of total vCJD cases for Saudi Arabia not greatly different from rates for several European countries

Overall risk for dietary exposure to BSE agent by the Saudi Arabian population as a whole, based on public information, less than that in UK

Since 1999, FDA used model to estimate risk of dietary exposure to BSE agent in various countries as % of risk in UK (risk in UK 1980-1996 taken to be 100%)

FDA adjusts recommended geographic deferrals taking into consideration risk relative to UK risk.

Caveat. Underlying information is highly uncertain.

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FDA previously recommended BSE-related deferral of certain blood donors based on estimated

geographic risk relative to UK risk 1980-1996

Main BSE risk of concern: eating UK beef Donor dietary histories not reliable Proxy for history of beef consumption: time donor

spent in BSE risk country Assumption: dietary risk is stochastic, directly

related to time spent in BSE country of concern Relative to UK 1980-1996 = 1.00

─ France = 0.05─ Switzerland = 0.015─Other Western European countries = Switzerland─ US military bases in Europe = 0.35

22

Estimating risk of exposure to BSE agent in Saudi Arabia 1980-1996

What might be a reasonable BSE-exposure risk estimate relative to UK and period of concern for donors resident in Saudi Arabia?

Saudi populations of concern 1980-1996

1. US military (very few US military dependents lived in Saudi Arabia)

2. US military contract workers and dependents

3. Non-military contract workers and dependents

4. Saudi nationals

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FDA current considerations regarding possible additional deferrals/ineligibility criteria for certain blood and HCT/P

donors resident in Saudi Arabia 1990-1996.1. US Military

US military in Saudi ArabiaFDA assumes that the risk of dietary exposure

to the BSE agent on Saudi bases was similar to the risk on US military bases in Europe South of the Alps = 35% UK risk 1980-1996.

DoD recently estimated that actual procurements of UK beef might have been somewhat less than on European bases.

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FDA current considerations regarding possible additional deferrals/ineligibility criteria for certain blood and HCT/P

donors resident in Saudi Arabia 1990-1996.1. US Military (2)

US military in Saudi Arabia 1980-1996 FDA currently recommends

deferral/ineligibility for donors of blood Source Plasma and HCT/Ps US military and dependents who spent 6 mo on bases South of the Alps 1980-1996.

New FDA consideration Recommend similar suitability criteria for

donors who served as US military personnel resident on Saudi bases 1980-1996

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2. Other residents of Saudi Arabia.Military and Non-military Contractors

and Saudi Nationals

FDA assumes that BSE exposure risk of all contract workers is similar to that for the general Saudi population, because they all purchased food from local (non-US-military) establishments.

Caveat: Diets and medical care of contractors might not have been the same as that of the general Saudi population, possibly resulting in

─? Greater consumption of all beef and UK beef

─? Greater likelihood of diagnosing vCJD

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2. Other Residents of Saudi Arabia.Saudi Nationals (2)

Dietary risk of BSE exposure by Saudi nationals was probably much lower than the risk for the UK population 1980-1996:

UK export/Saudi import records suggest only ~ 10% of Saudi beef imported from UK

Average per-capita beef consumption in Saudi Arabia ~ 25% UK

Total estimated Saudi dietary BSE exposure risk ~ 2.5% UK risk

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2. Other Residents of Saudi Arabia (3)Military and Non-military Contractors and Saudi Nationals

FDA assumes that risk of dietary exposure to UK beef by contract workers and Saudi nationals was similar to risk in non-UK Western European countries during years 1980-1996.

Non-UK countries of Western Europe with highest vCJD risk: France (and Ireland). A prudent precautionary assumption is that the risk in Saudi Arabia is unlikely to exceed the risk in France.

FDA assumes that BSE-exposure risk in Saudi Arabia, unlike France (which has had BSE in native bovines), is attributable almost entirely to imports of UK beef products, so that risk became negligible after the end of 1996.

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2. Other Residents of Saudi Arabia (4)

FDA currently recommends deferral/ineligibility for all donors of blood, Source Plasma and HCT/Ps who spent 5 yr in France (as well as for donors with history of transfusion in France) from 1980 to the present time.

New FDA consideration for non-US-military residents of Saudi Arabia

Recommend suitability/eligibility criteria for any donor of Whole Blood, Source Plasma or HCT/Ps who spent cumulative 5 years or longer in Saudi Arabia during the years 1980-1996 (similar to recommendations for residents of France but not extending to the present time and not including deferral for history of transfusion)

29

Geographic vCJD-related Blood Donor Deferralsin US and Canada

US FDAa

Canadian Blood

ServicesHéma-Québec

UK 3 mo 1980-96 3 mo 1980-96 1 mo 1980-96

France 5 yr1980-present

5 yr1980-present

3 mo1980-present

Other Western Europe (WE)

5 yr1980-present

28 countries

5 yr1980-present12 countries

6 mo1980-present12 countries

Hx of transfusion

UK, France1980-present

UK, France, WE 1980-present

UK, France, WE 1980-present

Saudi Arabia no deferral 6 mo 1980-96 6 mo 1980-96

a FDA recommends deferral of personnel resident on US military bases in Europe: North of Alps 1980-1990; South of Alps 1980-1996.

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Estimated Loss (under most likely scenario) of US Blood Donors/Donations Expected from Deferrals

for Residence in Saudi Arabia 1980-96 (Hong Yang/Steven Anderson OBE CBER FDA)

US MilitaryUS Military Contractor

s

USNon-

military Contractor

s

ImmigrantsSA to US Total

Population deferrable

420,000 0 45,900 24,800 490,000

Blood donors lost

21,000 0 2,300 1,200 24,000a

Blood units lost

35,700 0 3,910 2,040 41,700

a Estimated total US blood donors 2008 11 million. Most likely loss from deferrals for donors in Saudi Arabia 0.2%

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Conclusions

Three cases of vCJD are attributed to dietary exposures to BSE agent in Saudi Arabia 1980-1996.

Under current FDA recommendations, those donors would have been suitable/eligible donors of blood, plasma and HCT/Ps.

Crude prevalence of vCJD cases in Saudi Arabia is not markedly less than those in several European countries.

The most likely source of dietary exposure to the BSE agent in Saudi Arabia was imported UK beef.

32

Conclusions (2)

UK beef exports to Saudi Arabia ceased by the end of 1996.

FDA acknowledges a theoretical possibility that Saudi Arabia might have imported BSE-contaminated products from other countries after 1996 or introduced BSE into its own cattle herds; those are less likely sources of exposure.

33

Conclusions (3)

The US military procured an unknown but possibly significant amount of beef from the UK in 1980-1996 for bases in Saudi Arabia.

FDA considers a plausible worst-case assumption that the amount of UK beef consumed by US military in Saudi Arabia 1980-1996 might have been similar to that on European US military bases South of the Alps 1980-1996.

FDA assigned a geographical BSE risk of 35% UK risk 1980-1996 to European US military bases South of the Alps during the same years.

34

Conclusions (4)

FDA currently recommends deferral/ineligibility for donors of blood, Source Plasma and HCT/Ps who served in the US military and for their dependents who spent 6 mo on bases South of the Alps 1980-1996.

FDA is considering a recommendation to defer/consider ineligible donors who served as for 6 mo on US military bases in Saudi Arabia 1980-1996.

35

Conclusions (5)

At least 10% beef consumed by Saudi nationals living in Saudi Arabia 1980-1996 might have been imported from the UK.

Estimated per-capita beef consumption in Saudi Arabia appears to be less than that in UK (~25%).

FDA has tentatively assigned to Saudi Arabia a risk of dietary exposure to the BSE agent 1980-1996 = 2.5% that in the UK.

Contractors bought beef products in the same establishments as did Saudi nationals.

36

Conclusions (6)

FDA considers all contractors to have had the same potential risk of dietary exposure to BSE agent in Saudi Arabia 1980-1996 as did Saudi nationals.

Considering current estimates of crude prevalence of vCJD in Saudi Arabia compared with European countries, FDA considers it prudent to assume, as a realistic worst case, that true prevalence of vCJD in Saudi Arabia is unlikely to exceed that in France.

FDA believes that opportunities for dietary exposure to BSE agent in Saudi Arabia—unlike France—became negligible after the end of 1996.

37

Conclusions (7)

FDA currently recommends deferral/ineligibility for all donors of blood, Source Plasma and HCT/Ps who spent 5 yr in France 1980 to present

FDA is considering a similar recommendation to defer/consider ineligible donors of Whole Blood, Source Plasma and HCT/Ps who spent a cumulative period of 5 yr or longer in Saudi Arabia 1980-1996.

FDA estimates that the likely number of additional otherwise suitable blood donors who would be deferred under the new recommendations would be relatively small (perhaps 0.2% of current donors).

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TSEAC Voted1. Do available data support consideration by FDA

[because of analogy to risks in Western Europe]to recommend deferring donors of blood and blood

components, including Source Plasma, and to be ineligible donors of HCT/Ps who

Question Yes No Abstain

1)a( spent 6 mo as US military on KSA bases 1980-96? or

12 4 0

1(b) otherwise lived in KSA 1980-96? 15 1 0

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TSEAC comments on Question 1

More donors of Source Plasma might be deferred than donors of blood—should be estimated.

Since no cases of vCJD have been observed among more than 5 million former military who lived on bases in Europe and Saudi Arabia 1980-1996, the risk of BSE exposure has probably been overestimated.

US military procurement carefully excluded “specified risk materials” from imported UK beef, probably lowering dietary risk.

40

Questions for TSEAC (2)

2. Please discuss the likely contribution of those recommendations to the safety of the products involved and the possible impact on supplies of blood, blood components, plasma derivatives and HCT/Ps.

Members commented: Most risk is from inapparent infections in donors with less

susceptible genotypes (PRNP-129 MV and VV). Concern about lack of reliable data Concern about many other countries that probably

imported BSE-contaminated products but have questionable surveillance for BSE, vCJD. Donors resident in those countries are considered suitable.

41

Questions for TSEAC (3)

3. Please comment on additional information that might better inform FDA’s consideration of the proposed or any further safety measures.

Members commented:

There should now be sufficient empirical information (vCJD cases recognized in various risk groups) to revisit deferral/eligibility criteria and stop basing policy decisions on risk models where reliable observational data are available.

Continued and improved TSE disease surveillance efforts are important.

Risk-benefit of donor deferrals/eligibility criteria should be reevaluated.

Rapid testing for PrPTSE in brain tissues from cadaveric cell/tissue donors should be encouraged.