# Presentation: 711466

## Summary of Proceedings:FDA Transmissible Spongiform EncephalopathiesAdvisory Committee17th Meeting 08 February 2005

**FDA Blood Products Advisory Committee**
**82nd Meeting**
**17 March 2005**
**Gaithersburg MD**
**David M. Asher, MD**
**<asher@cber.fda.gov>**
**Laboratory of Bacterial, Parasitic and Unconventional Agents**
**Division of Emerging & Transfusion-Transmitted Diseases**
**Office of Blood Research & Review**
**Center for Biologics Evaluation & Research**
**US Food & Drug Administration**

## Slide 2

**Notes:**
Thank you and good morning.
The 17th meeting of the FDA TSE Advisory Committee took place on February 8.

## Worldwide BSE update (Lisa Ferguson, APHIS, USDA)
 UK notifications of recipients plasma derivatives re possible vCJD risk (Kate Soldan, Anna Molesworth, UK CJD Incidents Panel) [TSEs and surgical instrument decontamination (Lynn Sehulster, CDC)] 
Developing a risk assessment model and initial risk estimates for exposure to agent of variant Creutzfeldt-Jakob disease (vCJD) via investigational use of UK factor XI in USA (Mark Weinstein, Dorothy Scott, Steven Anderson, FDA)
Developing risk assessment models for exposure to vCJD agent via other coagulation factors (Steven Anderson, FDA)
vCJD in France (Jean-Philippe Brandel, EpidemioSurveillanceNetwork, Paris [presented in absentia and revised by Pedro Piccardo and Steven Anderson, FDA]) and UK (Sheila Bird, MRC Biostat Unit, Inst of Public Health, Cambridge)
Possible deferral of blood and plasma donors with history of prior transfusion in European countries besides UK (Alan Williams, FDA
----------------------------------------------------------------
= Decisional issues

** ****UK notifications of recipients plasma derivatives re possible vCJD risk ****(Kate Soldan, Anna Molesworth, UK CJD Incidents Panel)**** [TSEs and surgical instrument decontamination ****(Lynn Sehulster, CDC)****] **
**Developing a risk assessment model and initial risk estimates for exposure to agent of variant Creutzfeldt-Jakob disease (vCJD) via investigational use of UK factor XI in USA ****(Mark Weinstein, Dorothy Scott, Steven Anderson, FDA)**
**Developing risk assessment models for exposure to vCJD agent via other coagulation factors ****(Steven Anderson, FDA)**
**vCJD in France ****(Jean-Philippe Brandel, EpidemioSurveillanceNetwork, Paris [presented in absentia and revised by Pedro Piccardo and Steven Anderson, FDA]) ****and UK**** (Sheila Bird, MRC Biostat Unit, Inst of Public Health, Cambridge)**
**Possible deferral of blood and plasma donors with history of prior transfusion in European countries besides UK ****(Alan Williams, FDA**
**----------------------------------------------------------------**
**= Decisional issues**

**Notes:**
Three informational issues and three decisional issues—bullets bolded here—were reviewed, two for discussion and one for vote.
Lisa Ferguson reviewed the worldwide BSE situatio
Kate Soldan and Anna Molesworth of the UK Health Protection Agency/CJD Incidents Panel reviewed the Sept 2004 notification of certain recipients of plasma that they might be at increased risk for exposure to the VCJD agent and should not donate blood or tissues and should tell their families, dentists and surgeons to take special precautions to avoid 2o transmissions. Lynn Sehulster of CDC reviewed what such precautions might be, though CDC currently recommends them only for known TSE patients but not for instruments exposed to tissues of persons at increased risk.
You may recall from a statement I read at the last BPAC meeting, that UK FXI was used for a limited time in the USA under IND, and that situation was reviewed by FDA’s Mark Weinstein and Dorothy Scott, and the promised risk assessment model—I’ll summarize that briefly—by Steven Anderson, who
 ... also reviewed a draft risk model suitable for addressing risks from US factors VIII and IX.
FDA’s Pedro Piccardo and Steve then presented information on vCJD in France from J-P Brandel—who couldn’t attend.
Finally TSEAC reviewed and voted on the issue of possible deferrals of blood and plasma donors with a history of transfusion in Europe outside UK.

## Slide 4

**Notes:**
The news on BSE is guardedly good ... 

## Cases of BSE Registered in Great Britain through 1999 (DEFRA)

**Notes:**
After peaking in the UK at the end of  1993, cases in UK continue to drop ...

## Slide 6

**Notes:**
UK diagnosed 612 cases in 2002, and only 338 last year, though that still exceeded any other country.

## 23 Countries with BSE in Native Cattle[yr first reported & approx. total cases reported to OIE thro’ 28 Feb 2005]

**UK**** ****1986 ****(>183 000) [1202 ‘01;**** 1144**** ’02; 612 ’03; 338 ’04]**
**Ireland**** ****1989 (1489)**
**Switzerland**** ****1990 (519)**
**France**** ****1991 (945)**
**Portugal**** ****1994 (950)**
**Belgium**** ****1997 (129) **
**Netherlands**** ****1997 (77)**
**Luxembourg**** ****1997 (2)**
**Liechtenstein**** ****1998 (2)**
**Denmark ****2000 (13)**
**Germany**** ****2000 (357)**

**Spain ****2000 (519)**
**Italy ****2000 (124)**
**Greece ****2001 (1)**
**Czech Repub**** ****2001 (15)**
**Slovakia**** ****2001 (15)**
**Japan**** ****2001 (15)**
**Slovenia**** ****2001 (5)**
**Finland ****2001 (1)**
**Austria ****2001 (1)**
**Poland**** ****2002 (22)**
**Israel ****2002 (1)**
**Canada ****2003 (1 ex UK+4)**
**[USA ****2003 (1 ex Canada)****]**

**Notes:**
Diagnosed cases dropped about 40% in the rest of Europe; though six countries registered increases from 2003 to 2004, numbers were small, and it is not clear to me whether those increases are from better ascertainment or a trend in disease.
We are all aware of the Canadian BSE cases, and they were not discussed.
USDA has now completed more than 270,000 tests of brain from cattle identified as being at increased  risk for BSE, with three tests inconclusive by ELISA and none confirmed by immunohistochemistry.

## Total Reported UK Exports of MBM 1986 –1995(unconfirmed review by UK authorities of export records)

**Total Reported UK Exports of MBM 1986 –1995****(****unconfirmed review by UK authorities of export records)**

**Notes:**
Countries of unknown BSE status remain of concern. UK Customs and Excise information show that meat-and-bone meal was exported during high BSE years to a number of countries—several of which, like the USA, have, I understand, no record of receiving it. A number of countries in Southeast Asia and the Former Soviet Union may have imported substantial amounts, though that probably cannot be confirmed.

## Slide 9

## 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)

**Notes:**
In recent years, a second major concern has been about the risk for regulated products from human adapted BSE agent, causing variant CJD ...

## Variant CJD: Reasons for Greater FDA Concernabout Potential Infectivity of Blood

**Lymphoid tissues of patients with vCJD contain much more protease-resistant prion protein than do those of patients with conventional forms of CJD.  Infectivity of those tissues is not yet clear.  (Note: Lymphoid tissues of some patients with **_**conventional**_** sporadic CJD [sCJD] have been infectious for non-human primates [****Brown P et al. Ann Neurol 1994;35:513****].)**
**Implication:  Blood, containing lymphoid cells, might be more infectious in vCJD than in classical forms of CJD. **
**vCJD differs markedly from sCJD;  distribution of infectivity in patients with sCJD might not be predictive for vCJD.**
**vCJD is a new emerging disease not found in the USA except in one long-time UK resident.**
**Actions of UK authorities implied lack of confidence in safety of blood of UK donors.**
**----------------------------------------------------------------------------**
**Two cases of probable TT vCJD**

**Notes:**
Which differs significantly in clinical presentation, histopathology and epidemiology from other forms of CJD. Our concern was heightened by reports of two cases of blood-borne vCJD in December 2003 and July of last year, which have been described here before. Concern about the theoretical risk of transfusion-transmitted vCJD prompted FDA to issue revised guidance in 1999 and again in January 2002 ...

## Final Guidance for Industry:  Revised Precautionary Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) & Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood ProductsJan 9, 2002www.fda.gov/cber/guidelines.htm

_**Phase I**_** (for implementation by May 31, 2002)**
**Indefinitely defer all donors who**
**have any form of CJD or are at increased risk of CJD**
**(no change from previous FDA guidance)**** **
**spent ********3 mo in UK from Jan 1, 1980 to Dec 31, 1996 **
**or who ever had blood transfusion in UK from 1980 to present**
**or who ever injected UK bovine insulin prepared in or after 1980**
**spent ******** 5 yr in France from Jan 1, 1980 to the present**
**spent ********6 mo on US military bases from Jan 1, 1980 to end of 1990 north of Alps or end of 1996 south of Alps**

**Notes:**
I have included slides summarizing the latest revised guidance ...

## Final Guidance for Industry:  Revised Precautionary Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) & Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood ProductsJan 9, 2002www.fda.gov/cber/guidelines.htm

_**Phase II**_** (for implementation by October 31, 2002)**
**Indefinitely defer all donors of Whole Blood but not donors of Source Plasma who spent ********5 yr in Europe from Jan 1, 1980 to the present**** ****(including time in spent in UK 1980-1996 and France 1980-present)**
_**Exempt from deferral are**_
**Donors of Source Plasma who spent any period of time in Europe except UK and France**
**Donors of plasma/serum to manufacture CBER-approved non-injectable products (specially labeled)**

**Notes:**
... but most of you are familiar with it and we have discussed it here before.

## 170 Cases of vCJD Worldwide (end Feb 2005)

- 		**UK****	****	****	****	****	****154**
**	****	****France****	****	****   ****	****	****    9**
**	****	****Republic of Ireland****	**** ****	****    2**
**	****	****Italy****	****	****	****	****	****    1**
**	****	****USA****	****	****	****	****	****    1**
**	****	****Canada****	****	****	****	****    1**
**	****	****Saudi Arabia****	****	****	****    1 **
**	****	****Japan****	****	****	****	****    1**
**	**-------------------------------------------------------------
**Six cases of vCJD in ****France**** (6) and 1 in ****Italy ****had no history of travel to UK. Nine others were current or former UK residents/visitors. Case from Japan spent <1 mo in UK (? 24 da) during BSE-high-risk period (1989).**

**Notes:**
Worldwide, cases of vCJD continue to increase slowly, to a current total of 170 of which all but 16 are or were UK residents and only 8 had never been in the UK.

## Variant CJD in UK each Year since 1994(from Will RG, unpublished Oct 2003)New Cases                                        Deaths 

**Notes:**
New cases peaked in UK in 1999 and deaths in 2000, though those were all in persons hemozygous for the gene encoding methionine at codn 129 of the PRPP gene—a genotype known to have increased susceptibility to other forms of CJD, while troubling new information suggests that—as for other forms of CJD—persons of other genotypes are probably not absolutely resistant to the infection, though possibly with lower attack rates and longer silent incubation periods.

## Nine cases of vCJD in France 1994-2004(Epidemiological data from J-P Brandel)

**Onsets**

**Deaths**

**Notes:**
It is too early to detect any trend in France.

## 1st Transfusion-Transmitted Case of vCJD (UK Parliament 17 Dec 2003; CA Llewelyn & al. Lancet  2004;363:417-421)

_**March 1996**_
** ****Clinically healthy young blood donor donated Whole Blood to the UK National Blood Service.**
** ****RBC—not leukoreduced—transfused into 63 yr-old surgical patient.**
_**About March 1999**_** **
** ****Three yr later, donor developed signs of variant CJD, died; vCJD was confirmed by autopsy.**
** ****UK Transfusion Medicine Epidemiology Review (TMER) enrolled recipient (with 49 other recipients of vCJD-implicated labile blood components from 16 donors later Dx with vCJD—13 now living >5yr).**
_**December 2003**_
** ****The recipient died age 69; post-mortem diagnosis was typical vCJD (*****PRNP*****-129-met/met homozygous).**
** ****The recipient's age-adjusted food-borne risk of vCJD estimated by UK authorities to have been ~ 1:15,000 to 1:30,000.**

**Notes:**
Just in case there are specific questions, I again included in the set summary slides describing the two cases of presumptive transfusion-transmitted vCJD, both recipients of non-leukoreduced red blood cell concentrates.

## 2nd Transfusion-Transmitted Case of vCJD(Peden AH & al. Lancet 2004;264:527-529)

_**1999**_
** ****Clinically healthy young blood donor donated Whole Blood to the UK National Blood Service.**
** ****RBC—not leukoreduced—transfused into a  surgical patient.**
_**2000**_** **
** ****Donor developed signs of variant CJD 18 mo later, died in 2001; vCJD confirmed by autopsy.**
** ****UK Transfusion Medicine Epidemiology Review (TMER) enrolled recipient (with 49 other recipients of vCJD-implicated labile blood components from 16 donors later Dx with vCJD—13 now living >5yr).**
_**2003**_
** ****The recipient died of ruptured abdominal aortic aneurysm.**
** ****No history of dementia and CNS, tonsils and appendix  were normal. **
** ****PrP****sc**** was present in several areas of spleen, cervical lymph node.**
** ****The recipient's age-adjusted food-borne risk of vCJD was estimated by UK authorities to have been ~ 1:15,000 to 1:30,000.**
** ****Recipient’s genotype was *****PRNP***** **_**129-met/val heterozygous**_**).**

**Notes:**
The second case was of special interest, because that person—who died of unrelated causes during what is thought to have the asymptomatic incubation period of vCJD without CNS pathology but with accumulations of disease-related prion protein in spleen and a cervical lymph node—was the heterozygous individual I just mentioned.

## General Approaches to Assessing Risk

**FDA is committed to **
_**risk**_**-**_**based**_** regulatory decision making.**
**-----------------------------------------------------------**
**Recent Example:**
**TSEAC Meeting 08 February 2005**
**-----------------------------------------------------------**
**TSE Risk Assessment**
**for Plasma Derivatives**
**Steven Anderson, PhD, MPP**
**Office of Biostatistics & Epidemiology**
**Center for Biologics Evaluation and Research**
**U.S. Food and Drug Administration**
**-----------------------------------------------------------**
**<http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4088t1.htm>**

**Notes:**
Now to the FXI issue—a total of about 50 individuals in the USA treated with a UK FXI concentrate under IND from 1989 through 1997. No FXI used here was from an “implicated” lot—no donor has been diagnosed with vCJD. However, vCJD has a possible prevalence in the UK sufficiently high that it seems likely that some asymptomatic infected donors may have contributed.
Steven Anderson with Hong Yang and others in FDA has developed a risk model and preliminary exposure estimates for recipients of FXI in those studies.

## Risk of Product Contamination

_**Source of raw materials**_
**Animal: low-risk origin, low-risk tissue**
**Certificate**
**Test for contaminant or Dx (better ones needed)**
**Human: low-risk population**
**Donor or surrogate questionnaire**
**Donor screening test (needed)**
_**Manufacturing process**_
**Eliminate contaminating agent (validate method)**
**Inactivation**
**Removal**
**Prevent cross contamination (“downstream” contamination)**
**Cleaning**
**Disinfection**
_**End use of product**_
**Route**
**Dose (course, year, lifetime)**

**Notes:**
as promised at the last BPAC, presented it at the TSEAC. Also as promised, FDA has engaged in discussions with CDC about notification strategies and messages.
Risks for transmission of infectious agents by regulated products are often estimated—and later managed—by analysis of source of raw materials, the ability of manufacturing processes to inactivate a contaminating agent, and the amount of agent to which a recipient of the product is likely to be exposed.

## Factor XI Risk Assessment

- Log10 reduction ID50 during processing

- ivID50 per unit FXI
- ivID50 per vial
- Scenarios: include a pre- and post-surgery dose 20 – 50 u/kg

_**SOURCE**_
- vCJD ID50 plasma pool

_**PROCESS**_
- Reduction by manufacture

_**USE**_
- Dose per surgery

**Input**

**Module**

**Output**

- ID50 in FXI post-processing
- Yield FXI plasma pool
- Total ID50 per vial

- Exposure estimate   vCJD iv ID50
- Exposure estimates 3 scenarios

- Total i.c. ID50 per vCJD donation
- Total i.v. ID50 per plasma pool of 20,000 donations

- Probability vCJD in UK
- Number vCJD donations per pool
- ID50 per ml plasma

_**Factor XI Risk Assessment**_
**Exposure Assessment Overview**

**Notes:**
And Steve’s model—a quantitative or “probabilistic model—is organized in that way, looking at the source material, which was Recovered Plasma: the probability that a given donor was incubating vCJD, number of donations in each pool, as possible infectivity levs in the plasma,
... then the potential reduction in infectivity by manufacturing process, and

... finally the total amounts of infectivity to which recipients of product in three typical scenarios might have been exposed.

## UK vCJD prevalence affects the number of possible vCJD donations per plasma pool to manufacture Factor XI.

| 
Prevalence of vCJD in UK Population
Cases per million
(epidemiological survey,
? worst-case data)
 | 
Mean | 
95% confidence interval |
| --- | --- | --- |
|  | 237 | 49    to   692 |
| 

 |  |  |
| 
Triangular distribution
Parameters | Mean | Range |
| 
UK Plasma pool
Number of vCJD donations
per 20,000 donations 
 | 
~ 5

Most likely =2 | 0      to     14
 |

- Prevalence   x

- _2x10__4 _
- 106

- 1
- 50

**Notes:**
Modern probabilistic risk assessment account for biological variability and, especially for uncertainty of assumptions, assigning to most assumptions a distribution or range of values: Steve used so-called “triangular distributions” of most-likely, minimum and maximum values. Of course, the actual values assigned are always open to challenge, but the basic model allows for easy recalculation incorporating different values.
For example, based on a recent survey of abnormal  PrP in appendices—more about that in a minute—Steve assigned a most likely value of 2 for donors incubating vCJD who might have contributed to a pool 20,000 donations with a range of zero to 14.

##  UK FXI vCJD Exposure Assessment:Possible vCJD infectivity in UK plasma pool

_**Quantity**_** **_**of**_** **_**vCJD**_** **_**ID**_**50**** **_**present**_** **_**per**_** **_**ml**_** **_**plasma**_
**Intracerebral (ic) ID****50**** per ml blood (animal ID****50****)**
**Minimum 0.1**
**Most likely 10**
**Maximum 1,000 **
**Assume 58% associated with plasma ****(Gregori, et al. 2004)**
**Adjust down 5-fold to 10-fold for reduced efficiency of intravenous (iv) vs ic route of exposure**

**Notes:**
Based on animal studies, a broad range of 0.1 to 1000 icID50 per ml of infected blood with 10 most likely, but he used a point estimate of about 60 for percentage of infectivity in plasma and 5 to 10-fold reduction in infectivity to account for relative inefficiency of the intravenous route compared with intracerebral, since the preponderance of evidence supports those assumptions. 

## FXI vCJD Exposure AssessmentReduction during manufacturing PROCESS 

| 
Assumption | 
Minimum | 
Most Likely | 
Maximum
 |
| --- | --- | --- | --- |
|  |  |  |  |
| 
Log10 reduction
vCJD agent infectivity
 | 0 | 2.0 | 4.0 |

**Log****10**** reduction ID****50**** during plasma processing**
-  **Reduction based on processing steps**
** ****Variability in processing and reductions achieved**

**Notes:**
For reductions in infectivity by manufacturing of the FXI, based on published studies of other plasma derivatives, Steve assumed from none to to 10,000 fold, with 100-fold reduction most likely.

## Results of FXI Risk Assessment Model: Exposure to vCJD iv ID50(no conclusion about relationship between exposure and infection)

|  Scenario |  Quantity of factor XI utilized  |  Mean vCJD
iv ID50  |  5th 
percentile  |  95th 
percentile  |
| --- | --- | --- | --- | --- |
|  |  |  |  |  |
| A single unit FXI | 1 u | 2 x 10-5  |  6.8 x 10-7  | 7.0 x 10-5  |
| One vial FXI | 1,000 u | 2 x 10-2   |  6.8 x 10-4  | 7.0 x 10-2  |
| Scenario 1: 
1 treatment 60 kg person  | 3,000 u | 6 x 10-2  |  2.1 x 10-3   | 0.21   |
| Scenario 2: 
3 treatments 60 kg person 
 | 9,000 u | 0.17 | 6.2 x 10-3  | 0.6  |
| Scenario 3:  
>3 treatments 60 kg  person  | 15,000 u | 0.28   | 1.0 x 10-2   | 1.0  |

**Notes:**
The uncertainties of the results must not be dismissed.

For example, for  Scenario 3 , in which a subject received 15,000 units of FXI, there might have been a mean estimated exposure to 0.28 vCJD ID50—suggesting a chance that 14%  (50% of 0.28) individuals that received a dose of Factor XI from the UK were exposed to and some infected with vCJD.  However, animal data may not accurately reflect the potential for vCJD infection and illness in humans.  Those uncertainties are no less important than the computer generated “most-likely” risk estimate.
CDC has pointed out that the BSE outbreak was identified in the UK in 1986 and peaked about seven years later—ample time for human plasma derivatives to have been implicated in transmitting vCJD—yet not a single case has been attributed to any derivative, which gives reason to hope that the estimates might be too high.

## Exposure RisksAdvantages of quantitative models

_**Transparent:**_** assumptions articulated and available for modification**
_**Data**_** **_**gaps: **_**identified**
_**Sensitivity**_** **_**Analysis**_** (Importance Analysis): Most important elements “driving” overall risk identified, even without agreement on assumptions**

**Notes:**
But quantitative risk analyses have advantages. Transparency: If you distrust  the assumptions, ones you prefer can be incorporated, and, in response to suggestions from TSEAC, Steve is adjusting vCJD prevalence assumptions to allow for differences in subject ages and years studied in the tissue survey he used and ages for FXI plasma donors and years of donation.
Data gaps are easily identified—I’ll might show some of those.
And, by holding the magnitudes of all assumptions constant except one and then systematically increasing each separately and examining final estimated risk values—called Sensitivity or Importance Analysis—the critical drivers of risk can be identified.

## vCJD DATA GAP: PREVALENCE

**Epidemiological Models**
**Predicting the Size of the UK vCJD Epidemic**
**(from R Will, thro Oct 2003)**

- (Cousens)

- (Ghani)

- (Ghani)

- (Ghani)

- (d’Aignaux)

- (Valleron)

- (Boelle)

- (75)

- (80,000)

- (29)

- (13.7 million)

- (52)

- (6.1 million)

- (63)

- (136,000)

- (200)

- (3,000)

- (205)

- (183)

- (416)

**Notes:**
Data gaps. Based on models, predictions of vCJD prevalence in UK—total cases to be expected in their population—offered since 1997 have varied from a minimum of  29 (154 already, so that can’t be right) to 13.7 million, most recently from a few hundreds.

## PrPsc in Appendix, Tonsils: Association with vCJD(Hilton DA et al.  Brit Med J 2002; 325: 633-634, J Pathol 2004;203:733-739) 

**Estimated UK prevalence of abnormal PrP in lymphoid tissues**
**1****st**** survey: ~120/million (95% CI   0.5 – 900/million)**
**2****nd**** survey: ~237/million (95% CI 49-692/million)**

- *1 yr, 2 yr,10 yr (neg) before onset of symptoms; 3 yr, 4 yr, 11 yr (neg) before death

| Postmortem vCJD | 19/20 |
| --- | --- |
| Preclinical vCJD | 2/3 |
| 1st Surgical Survey | 1/8318 |
| 2nd Surgical Survey | 3/12,674 |

**Notes:**
But results of a recent survey of  scrapie-type prion protein in tissue from routine  appendectomies in the UK, suggested that more than 100 persons per million in UK might be in preclinical incubation period of vCJD suggesting that several thousand people there might eventually get the disease.
Many authorities suspect that those figures are too high, but it seems prudent at least to include them as examined assumptions in any risk analysis. 

## vCJD Data Gaps:

**Incubation periods, duration of blood infectivity, amounts infectivity in blood, human ivID50) **

** **_**Incubation**_
** **_**Food-borne**_** **_**cases**_
**US ****	****	****	****  ****	****   9-21 yr**
**Canada****	**** ****	****	**** 11-19 yr**
**Japan****	****	****	****      12 yr**
**[Ireland****	****	****	****   5-10 yr]**
** **_**Blood-borne**_** **_**cases**_
**First case ****	****	****   ****	****         6 yr**
**Second case ****	****	****      > 5 yr**
** **_**Blood**_** **_**infectivity**_** before clinical vCJD: ******** 3 yr****	****	**

**Notes:**
Some data gaps are slowly filling:
Intervals between former residence in UK and onset of vCJD suggest minimum incubation periods for food-borne disease of nine to 12 years. There was a six-year incubation for the first transfusion-transmitted case.
Blood of the first implicated donor was apparently infectious for at least three years before onset.
However, in order to estimate risk from plasma derivatives better, we need to know more—amounts of agent present in plasma and how that relates to the dose needed to infect recipients exposed by the intravenous route.

## Sensitivity Analysis: Risk DriversEstimates of FXI vCJD Exposure Risk

_**Two**_** **_**major**_** **_**factors**_** **_**influenced**_** **_**FXI**_** **_**vCJD**_** **_**risk:**_
**Number of vCJD donations per plasma pool**
**Risk reduction measure=donor deferrals**
**Reduction of vCJD agent during manufacture**
** ****Robustness (inactivation>removal)**
**Orthogonality (****≥****two processes preferred)**
** ****Additivity of process steps (must justify)**
** ****Validity (and relevance) of experimental data**

**Notes:**
Sensitivity Analysis confirmed intuitive suspicions of the two most important drivers of vCJD exposure risk: prevalence of infection (with infectivity in blood) in donors and reduction in infectivity by manufacturing.

## Recipients surviving >5 yrs post transfusion of blood components from vCJD/CJD Donors(data from UK TMER and US ARC look-back studies [R Dodd],presented by 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 of difference by chance).**
**Conclusion: **_**Risk**_** **_**of**_** **_**TT**_** **_**CJD**_** **_**is**_** **_**less**_** **_**than**_** **_**TT**_** **_**vCJD**_**.**

|  | Infection | No
Infection |
| --- | --- | --- |
| vCJD | 2 | 13 |
| CJD | 0 | 116 |

**Notes:**
I mentioned this at previous meetings, but it is important enough to repeat, considerably longer experience with blood components from donors who later got forms of CJD other than variant CJD has failed to identify any case of presumptive transmission. Variant CJD clearly carries a much greater risk of blood-borne transmission.

Anyhow, TSEAC discussed the risk model for FXI proposed by FDA and the developing models for other plasma derivatives, endorsed their overall design and suggested modifications to assumptions. 

## Policies to Reduce Risk of Transmitting vCJD by Blood Products by Donor Selection:General Approaches

**Reduce risk that donor was exposed to BSE agent**
_**Dietary**_** **_**exposure**_**: Lived in BSE country (or military base importing beef from UK) =“geographic” deferrals**
_**Other**_** **_**exposure**_**: Use of UK bovine insulin**
**Reduce risk that donor was exposed to vCJD agent of human origin**
_**Transfusion**_**, UK after 1980**
**[Transfusion, other BSE country—especially France]**
**[Surgery in BSE country after 1980: suggested by TSEAC member (not addressed by FDA or TSEAC)]**

**Notes:**
As you know, FDA has recommended CJD/vCJD blood safety policies to reduce the risk that a donor might be incubating CJD of any kind while not deferring so many donors as to compromise the supply of blood products. (We acknowledge that the policies cannot eliminate all conceivable risk.)
In October 2004, without offering specific options to consider, we asked to consider general types of precautionary deferral already in place and consider which, if any, are amenable to enhancement—reducing risk sufficiently to justify an inevitable loss of otherwise suitable donors (a precious resource).
Deferrals for potential dietary or other exposure to BSE agent. Possible enhancements to the current geographic deferrals (ignoring the taking of individual dietary histories—generally thought to be unreliable) would be to reduce the time that a suitable donor might have spent in various countries or to add new countries to the list. (Regarding non-dietary BSE exposures, we are not aware of any other UK bovine-derived injected product similar to insulin that was in general use.)
Deferral for history of exposure to human blood or blood products from donors potentially incubating vCJD. The enhancement would extend deferral to donors transfused in places other than the UK.

## Estimated vCJD Blood Risk Reduction and Donor Loss from Possible Enhanced Deferral Policies(from A Williams, FDA, TSEAC 14 Oct 2004)

|  | Reduced Risk  (in add’n to current 91%) | Donor Loss
(in add’n to current 6.4%) |
| --- | --- | --- |
| UK 3 mo (’80-96) 
 to 1 mo | 4% | 3% |
| Transfusion in France (’80-now) | Uncertain but
very small | 1.4/10,000 |
| Transfusion in Non-UK W Eu (’80-now) | Uncertain but
very small
(Problem: EuroBlood) | 3/10,000 |

**Notes:**
Alan Williams presented then and repeated at the February TSEAC meeting, the estimated reductions in risk and loss of donors that might result from three new policies, summarized here:
As usual, reducing time a suitable donor spent in UK reduces risk most but costs many donors. If we attempted to defer any donor who spent any time in UK 1980-1996—and Japan has just implemented such a policy—the donor loss is estimated to be  23% (and for any BSE country of Europe  36%).
Deferring blood donors transfused in France would reduce risk slightly at a cost of 1.4 donors and for the rest of Europe 3 donors per 10,000—minimal losses. Of course most US donors previously transfused  with European blood—from US-licensed establishments in Netherlands, Germany and Switzerland—got it in the New York City area EuroBlood program. Those recipients cannot be traced or deferred without deferring all other donors in that area, a doubtful prospect that Alan Williams discussed but I will not.

## TSEAC Advice to FDA 14 October 2004

**Are measures currently recommended by FDA to reduce the risk of transmitting CJD and vCJD by blood products still justified?**
**	****	****	****	****	**_**Yes 14,**_** **_**No 0**_
**Do recent scientific data on vCJD warrant consideration by FDA of any additional potentially risk-reducing measures for blood and blood products?**
**	****	****	****	****	**_**Yes 1,**_** **_**No 13**_
- If so, please comment on the additional risk-reducing measures that FDA should consider at this time. [Investigate vCJD cases **outside** UK for ? exposure to blood. Consider deferral of donors transfused in non-UK BSE countries.]

**Notes:**
In October, TSEAC was asked, without offering specific options
 to consider whether the CJD/vCJD deferral policies currently recommended by FDA to protect the safety of the blood supply remain justified and, 
if so and considering recent additional information about BSE and vCJD, they are still adequate.
TSEAC unanimously endorsed the current 2002 CJD/vCJD blood safety guidance and did not recommend any enhancements. However, in associated discussions, the members seemed concerned about the growing number of cases of vCJD in France and the higher BSE esposure risk there from major imports of UK beef products.
So at the Feb TSEAC meeting, we offered specific options for enhancement.

## TSEAC Advice to FDA 08 February 2005

**Should FDA recommend deferral of Whole Blood donors transfused after the beginning of 1980?**
**In France    ****	****	**_**Yes 12,**_** **_**No 3,**_** **_**Abstain 1**_
**Other W Europe****	****	**_**Yes 0,**_** **_**No 15,**_** **_**Abstain 1**_
**Should FDA recommend deferral of Source Plasma donors transfused in/after 1980?**
**In France    ****	****	**_**Yes 5,**_** **_**No 7,**_** **_**Abstain 4**_
**Other W Europe****	****	**_**Yes 0,**_** **_**No 16,**_** **_**Abstain 0**_** **

**Notes:**
The members voted overwhelmingly to recommend deferral of donors transfused in France from 1980 to the present. They split narrowly on whether to defer plasma donors with that history, with an unusually large umber of abstentions.
No member felt that deferral of blood or plasma donors transfused elsewhere in Europe outside UK and France was advisable.

## Limitation of deferral-based approachesto reduce the risk of blood-borne vCJD

_**Problem**_
**Many (? most) deferred donors are probably **_**not**_** infected with a TSE agent (needlessly deferred and alarmed).**
_**Possible**_** **_**solutions**_
**Develop validated and reliable screening tests to detect infected donors and re-enter/reassure uninfected donors.**
**Develop validated and reliable methods to remove (inactivate or separate) infectious TSE agents from products.**
_**Current**_** **_**status**_
**No FDA-licensed/approved TSE test (for diagnosis or donor screening)**
**No FDA-licensed method validated to remove TSE infectivity from red cells, platelets and plasma**

**Notes:**

We realize that BSE/vCJD risk reduction by deferral is inherently wasteful and look forward to the day—until BSE and vCJD are eradicated—when screening tests can identify those rare donors actually infected and methods are validated to remove TSE agents/prions from plasma and other blood components. Interesting progress in both technologies have been presented to TSEAC, and I understand that BPAC may hear about one possible removal technology later today.
But, at the moment, there is still no FDA-licensed screening test for infected donors or agent removal method. We encourage further development of both and anticipate their eventual submission to the agency for review.

Thank you.

## Slide 37