# Presentation: 820613

## Update onBovine Spongiform Encephalopathy

**FDA TSE Advisory Committee Meeting**
**Holiday Inn**
**Gaithersburg MD**
**20 February 2003**
**David M. Asher, MD**
**<asher@cber.fda.gov>**
**Laboratory of Bacterial, Parasitic & Unconventional Agents**
**Division of Emerging & Transfusion-Transmitted Diseases**
**Office of Blood Research & Review**
**Center for Biologics Evaluation & Research**

**Notes:**
Thank you.

## BSE Update

- Variant CJD: cases, trends, implications
- BSE:
- World distribution
- New countries
- Risk assessments (USDA, EC GBR)
- WHO warning
- Control measures
- Additional measures to protect human food
- EC and national actions on animal TSEs
- EC legislation
- National actions (example)
- Compliance?

**Notes:**
In TSEs of some animals—including mice, monkeys and sheep experimentally infected with the BSE agent—small amounts of infectious agent can be detected in the blood, first appearing during the long asymptomatic incubation period.  That finding, taken together with the fact that small amounts of agent are widely distributed in tissues of people dying of CJD—not just in their brains—suggested that human blood must be considered a potential source of infection.  Accumulating epidemiological evidence is reassuring, suggesting that blood-borne transmission of CJD in humans—if it occurs—must be too rare to detect retrospectively.  But common sense dictates that, if the agent is regularly present in blood of animals with TSEs, the same thing might happen occasionally in humans; at least the possibility must be considered.
Let me review briefly several aspects of the efforts taken to control BSE, to protect humans from exposure to the BSE agent, and hence to reduce the theoretical risk of transmitting infection through human blood.  I will summarize a CBER Guidance Document recommending precautionary steps to reduce TSE blood risk, noting that plasma derivatives appear to pose a lower risk than do blood components, steps needed to prevent human exposure to the BSE agent in food in those countries where the disease occurs, and end with a few comments concerning the risk posed by tissue products.  I may also comment on some recent research findings and events affecting public health before closing with a lesson from the past demonstrating the success of a regulatory action in ending a TSE epidemic—kuru. 

## 141 Cases of Probable or Confirmed Variant CJD (vCJD) in Six Countries[through Jan 2003]

- UK - 131 (total definite+probable; 119 dead)
- France - 6
- Ireland – 1*
- Italy - 1
- US – 1*
- Canada – 1*
- [Spain – 1* possible, under investigation]
- ---------------------------------
- *  Long-time UK residents

**Notes:**
Since the new variant of CJD was first reported and presumptively attributed to infection with the BSE agent, a total of more than 130 cases have been described in seven countries, most in current or former UK residents—including one in the US and one in Canada—but also several in persons who had never been in the UK.

## Age Distribution of CJD in UKCJD and vCJD 1994-2001(Taffs R & al.  FDA Science Forum 2002)

**Notes:**
At first some skeptics expressed doubt that variant CJD was really new or caused by the BSE agent, though all public health and regulatory authorities of which I am aware—certainly the FDA and other US Government agencies—immediately concluded that BSE must be considered the presumptive source of vCJD unless proven otherwise.

## 130 vCJD Cases in UK

**(Will R et al, CJD Surveillance Unit, Edinburgh, unpublished)**

- Mean age at death:	             29 yr (range 14-74)
- Median age at death:             28 yr
- Mean age at onset:                 27 yr (range 12-74)
- Median age at onset:              26 yr
- Median duration of illness:	   14 months (range 6-39)
- 72 males: 58 females
- 111 UK cases tested were MM at codon 129 of the PrP-encoding (PRNP) gene. Of 139 worldwide cases, 121 tested were MM at codon129 of the PRNP gene.

## Slide 6

**Notes:**
In that regard, there is some concern that the overall annual rates for diagnosed cases of sporadic CJD have increased in both the UK and Switzerland in recent years.  That may be due to better case finding but it may also reflect a real increase in incidence.

## 22 Countries with BSE in Native Cattle[yr first reported & approx. total cases reported to OIE thro’ Jan 2003]

**UK****  ****1986 ****(>182 581) [1443 in 2000; 1202 in ‘01;**** ****755 in ‘02]**
**Ireland**** ****1989 (1150)**
**Switzerland**** ****1990 (420)**
**France**** ****1991 (692)**
**Portugal**** ****1994 (699)**
**Belgium**** ****1997 (98) **
**Netherlands**** ****1997 (52)**
**Luxembourg**** ****1997 (2)**
**Liechtenstein**** ****1998 (2)**
**Denmark ****2000 (10)**
**Germany ****2000 (235)**

**Spain ****2000 (210)**
**Italy ****2000 (56)**
**Greece ****2001 (1)**
**Czech Repub ****2001 (2)**
**Slovakia ****2001 (10)**
**Japan ****2001 (7 or ?8)**
**Slovenia ****2001 (2)**
**Finland ****2001 (1)**
**Austria ****2001 (1)**
**Poland ****2002 (4)**
**Israel ****2002 (1)**

**Notes:**
In 22 countries with BSE affecting native cattle, the vast majority of cases—more than 182,000—have occurred in the UK.

## Slide 8

**Notes:**
Cases in the UK peaked near the end of 1992—about five years after authorities implemented effective controls prohibiting the use of meat-and-bone meal in cattle feed.

## BSE Incidence per 106 Cows > 24 mo old

**Notes:**
However, the recent incidence of BSE in British cattle, although only about 3% of that in the peak year, is still almost double that in Portugal and four times that in Ireland—the countries with the next largest number of cases.  Also disturbing is the fact that a number of cases have occurred in cattle born in the UK after full implementation of the feed ban in 1996—cases not attributable to maternal infection.  Some newer BSE countries may not yet have full implemented controls on animal feeds or efforts to protect the human food supply, and cases in those countries—although fewer in number than those in UK—may not yet have peaked.  So uncertainties remain about the risk of human exposure to the BSE agent in many countries.  It also seems likely that there are other countries with undetected cases of BSE in cattle—countries that imported and used contaminated feed ingredients but for one reason or another have not recognized BSE.

## Opinion of the Scientific Steering Committee [of the EC Directorate General SANCO] on theGeographical Risk of Bovine Spongiform Encephalopathy (GBR)adopted 11 January 2002 (modified from Final Opinion of July 2000)

- Qualitative method to assess BSE risk in regions or countries
- Not intended to assess human exposure risk
- Voluntary submission of dossiers by countries
- Systematic evaluation of risk factors by expert committees
- Dynamic risk: changes as situations change

## EC Geographical Risk of Bovine Spongiform Encephalopathy (GBR):Eight Risk Factors to Consider

- Cattle population and dynamics
- Trade in animals
- Animal feed controls
- Prohibition of meat-and-bone meal
- Specified risk materials controlled
- Surveillance
- Controls on rendering and feed preparation
- Culling of sick and at-risk animals

## EC Geographical Risk of Bovine Spongiform Encephalopathy (GBR):Two Main Composite Factors to Consider

- _External challenge_ (probability that BSE agent entered a country)
- Live cattle imports
- Meat-and-bone meal imports
- _Internal Stabilit_y (probability that BSE agent would amplify and spread in a country)
- Feeding practices: MBM ban in place
- Rendering practices
- SRM removal
- Surveillance of BSE
- Cross-contamination controls

## EC GBR Assumptions

- BSE is restricted to bovines among food animals
- Theoretical risk of infection of sheep and goats acknowledged but ignored
- Only sources of BSE agent are imports of infected cattle or bovine-derived materials
- Theoretical risk of spontaneous generation of infectivity ignored
- Transmission vector is contaminated feed
- Theoretical risks of maternal, contact, field contamination ignored
- Surveillance systems have intrinsic limitations
- Risk assessment cannot rely on confirmed cases

## Definition of the Geographical BSE Risk & its levelsUpdate of the Opinion of the Scientific Steering Committee [of the EC Directorate General SANCO] on the Geographical Risk of Bovine Spongiform Encephalopathy (GBR) adopted 11 January 2002 (modified from original Final Opinion of July 2000)

| 
GBR level | Presence of one or more cattle clinically or pre-clinically infected with the BSE agent in a geographical region/country  |
| --- | --- |
| I | Highly unlikely |
| II | Unlikely but not excluded |
| III | Likely but not confirmed or confirmed at a lower level |
| IV | Confirmed at a higher level |

## Two EC GBR IV Countries

- United Kingdom
- Portugal (mainland)

## 31 Countries in EC GBR III

- Albania
- Austria
- Belgium
- Bulgaria
- Croatia
- Cyprus
- Czech Republic
- Denmark
- Finland
- France
- Germany
- Greece
- Hungary
- Ireland (Republic)
- Israel

- Italy
- Japan
- Latvia
- Lithuania
- Luxembourg
- Malta
- Netherlands
- Poland
- Romania
- San Marino
- Slovak Republic
- Slovenia
- Spain
- Switzerland
- Turkey

## Nine Countries in EC GBR II

- Canada
- Colombia
- India
- Kenya
- Mauritius

- Nigeria
- Pakistan
- Sweden
- USA

## 17 Countries in EC GBR I

- Argentina
- Australia
- Botswana
- Brazil
- Chile
- Costa Rica
- El Salvador
- Namibia
- New Zealand

- Nicaragua
- Norway
- Panama
- Paraguay
- Singapore
- Swaziland
- Uruguay
- Vanuatu

## Predictive Record of EC GBR

- Correctly predicted case of BSE in native _cattle (GBR III_)
- Germany
- Italy
- Spain
- Czech Republic
- Slovak Republic
- Denmark
- Greece
- Japan (would have)
- Israel (would have)

- Did not correctly predict BSE in native cattle (originally assigned _GBR II)_
- Austria
- Finland
- Slovenia

## Measures to protect humans from food-borne exposures to BSE agent(FDA TSEAC Jan 2002)

_**Effective control of BSE in cattle and small ruminants**_** (sheep and goats)**
**OIE-compliant national surveillance programs (“Active” surveillance = testing of brain tissues from animals at increased risk of BSE)**
**Prohibitions on feeding most mammalian proteins to ruminants (“feed bans”) and steps to prevent accidental feeding of prohibited proteins**
**Prompt condemnation and destruction of animals with signs of BSE**
**Preventive culling of animals at increased risk**
**Adequate compensation to owners (encourages compliance)**

**Notes:**
Effective control of BSE in affected countries must include having an active surveillance system, prohibition on feeding of most mammalian proteins to cattle, efforts to avoid accidental contamination of feeds, prompt removal of animals with signs of illness that might be BSE, preventive culling of animals at increased risk of BSE, and compensation for owners to encourage their cooperation with the control program.
Because sheep and goats are susceptible to experimental infection with BSE agent and some unknown number were fed contaminated meat-and-bone meal, the UK has also implemented feed controls and other precautionary steps for those animals, but I will not discuss that today.

## Measures to protect humans from food-borne exposures to BSE agent(TSEAC Jan 2002 continued)

_** **__**Age-based slaughter schemes**_
**Intended to reduce risk by prohibiting consumption of meat products from ruminants slaughtered after an age when substantial amounts of BSE agent are likely to be present in tissues, generally taken to be no later than 24 to 30 months for cattle**
**Example:   **_**UK “Over-Thirty-Month” Rule**_

**Notes:**
Also important are so-called “Age-based Slaughter Schemes” like the prohibition in the UK against human consumption of meat from cattle older than 30 months (or 24 months in some other European countries).

## Measures to protect humans from food-borne exposures to BSE agent(TSEAC Jan 2002 continued)

_**Separation of high-risk materials from edible meat products**_
**Prohibition of slaughter methods that may embolize brain tissue, possibly contaminating meat, e.g. intracranial air injection and “pithing”**** **
**Removal of “specified risk materials” (SRM=CNS, lymphoid, intestinal tissues) from ruminant carcasses at the time of slaughter and effective segregation of SRM from edible materials**
**Prohibition of “advanced” or “mechanical” meat recovery systems (may contaminate meat with ganglia, spinal cord, possibly brain)**

**Notes:**
It has also been prudent to enforce steps—listed here—to reduce the likelihood that meat will be contaminated with brain, spinal cord or spinal ganglia during or after slaughter.

## Measures to protect humans from food-borne exposures to BSE agent(TSEAC Jan 2002 continued)

**A****pplication of same measures to protect the human food chain to imported food and domestically produced food**
**Effective compliance with all above to be verified by**
**Inspections**
**Audits**

**Notes:**
UK import controls have been sufficient to detect residual spinal cord in imported carcasses and to reject them.
Again, CBER is aware that these are risk-reducing and not risk-eliminating measures.  However, UK regulatory actions have clearly eliminated most, although not all, BSE infections of cattle, and there is no reason to doubt that, after 1996, the risk of human infections has been markedly reduced as well.
I remain confident that, if we find that the US blood supply has been compromised by the new CBER policies and cannot be replaced by active recruitment of new suitable donors and increased donations by repeat donors, our Agency will respond with the same appropriate flexibility that it has shown in the past to achieve maximum TSE risk reduction while maintaining an adequate supply.

## WHO Suggests Eight Questions from Consumers for National Authorities(“Understanding the BSE Threat” WHO 2002) 

- What are cattle fed?
- Is there active surveillance for BSE?
- Are cases of BSE imported or born in the country’s own herd?
- Does meat come from young cattle?
- Are high-risk tissues removed and destroyed?
- Are procedures in place to prevent cross-contamination?
- Are there any other meat products that could contain BSE [agent]?
- Are safe practices stringently controlled?

## Regulation (EC) No 999/2001 of the European Parliament and of the Council of 22 May 2001laying down rules for the prevention, control and eradication of certain transmissible spongiform encephalopathies

- Applies to production and marketing of live animals and animal-derived products.
- Applies to products intended for food, feed, fertilizer.
- Does not apply to cosmetics, medicinal products or medical devices (other rules apply).
- Rules apply to all EC Member States

## Regulation (EC) No 999/2001

- _Member States “should”_
- Monitor BSE and scrapie in annual active programs to include rapid [PrPTSE] tests.
- Designate, remove and safely dispose of SRMs.
- Prohibit feeding of certain proteins to certain animals.
- Notify authorities of suspect TSE animals and quarantine carcasses until diagnosis.
- Destroy TSE carcasses and identify other animals at risk, restrict their movements and compensate owners.

## Regulation (EC) No 999/2001 (continued)

- _Member States “should” also_
- Prohibit marketing of certain products from bovines in high-risk regions but allow certain products produced under controlled conditions from animals demonstrated not posing high risk.
- Establish Reference Laboratories for TSE tests including rapid [PrPTSE]  tests.
- Carry out inspections and audits of EC Member States and “third” countries.
- Reassess BSE status when OIE develops suitable procedures (proposes 5 categories instead of GBR I-IV).

## Regulation (EC) No 999/2001 (Annex)

- _Five EC Proposed BSE categories_
- BSE-free: No BSE, no risk, all requirements met 7 yr, no MBM in feed  8 yr.
- Provisionally BSE-free: No indigenous BSE [but history of risk] and compliant as for 1).
- Similar to 2) but with a few indigenous cases of BSE 7 yr ago and compliant but not for 7 yr [&c]
- Low BSE incidence: 1/106 but 100/106 animals 24 mo old.
- High BSE incidence: 100/106 animals 24 mo old.

## Example of National ActionAgence Française de Sécurité Sanitaire des Aliments (AFSSA):  Recent Opinions on Animal TSEshttp://www.afssa.fr/avis/index.asp?id

- _2001 (33 opinions)_
- _2002 (26 opinions [very loosely translated])_
- 3 Jan 		BSE control
- 16 Jan		Animal feeds
- 10 Feb		TSEs of small ruminants
- 6 Mar		Beef labels
- 12 Mar	Farmed game meat
- 25 Mar	Traceability of sheep and goats
- 28 Mar	Slaughter houses
- 28 Mar	Modified TSE orders
- 16 Apr 	Swiss cattle

## Agence Française de Sécurité Sanitaire des Aliments (AFSSA):  Recent Opinions on Animal TSEs (continued)

- _2002 _
- 25 Apr		Fertilizers
- 7 May		Transport of animal products
- 16 May	Transport of food
- 31 May	Comment on Bosque & al (TSE infectivity 					in rodent muscle)
- 31 May	Screening tests for small ruminants
- 13 June	Survey SRM retrieval in slaughterhouses
- 18 June	Mechanical meat recovery
- 27 June	Spinal cord removal from small ruminants
- 24 July	Animal feeds

## Agence Française de Sécurité Sanitaire des Aliments (AFSSA):  Recent Opinions on Animal TSEs (continued)

- _2002 _
- 27 Aug	Sanitary meat production, m’kting (mod.)
- 5 Sept		D”o and slaughterhouse inspections
- 19 Sept	Risk assessment for beef
- 9 Oct		Proposed modification of BSE controls
- 15 Oct		Proposed modification of UK imports
- 4 Nov		Scrapie control measures
- 14 Nov	Marketing of scrapie contact sheep/goats
- 20 Dec	Proposed rule change regarding direct 			sale of sheep and goat carcasses containing 		spinal cord

## Useful web addresses for BSE information (partial listing)

**European Commission **_[http://europa.eu.int/comm/food/fs/bse/index_en.html](http://europa.eu.int/comm/food/fs/bse/index_en.html)_
**France **_[http://www.afssa.fr/avis/index.asp?id](http://www.afssa.fr/avis/index.asp?id)_
**Switzerland **_[http://www.bvet.admin.ch/index_bse.html](http://www.bvet.admin.ch/index_bse.html)_
**UK Food Standards Agency **_**http://**__[www.foodstandards.gov.uk/bse/facts](http://www.foodstandards.gov.uk/bse/facts)_
**WHO **_[http://www.who.int/emc/diseases/bse/index.html](http://www.who.int/emc/diseases/bse/index.html)_

**Notes:**
UK import controls have been sufficient to detect residual spinal cord in imported carcasses and to reject them.
Again, CBER is aware that these are risk-reducing and not risk-eliminating measures.  However, UK regulatory actions have clearly eliminated most, although not all, BSE infections of cattle, and there is no reason to doubt that, after 1996, the risk of human infections has been markedly reduced as well.
I remain confident that, if we find that the US blood supply has been compromised by the new CBER policies and cannot be replaced by active recruitment of new suitable donors and increased donations by repeat donors, our Agency will respond with the same appropriate flexibility that it has shown in the past to achieve maximum TSE risk reduction while maintaining an adequate supply.