Update on Bovine Spongiform Encephalopathy FDA TSE Advisory

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

BSE Update l l Variant CJD: cases, trends, implications BSE: - l 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?

141 Cases of Probable or Confirmed Variant CJD (v. CJD) 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

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

130 v. CJD Cases in UK (Will R et al, CJD Surveillance Unit, Edinburgh, unpublished) Mean age at death: 29 yr (range 14 -74) Median age at death: 28 yr Mean age at onset: 27 yr (range 12 -74) Median age at onset: 26 yr Median duration of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 Pr. P-encoding (PRNP) gene. Of 139 worldwide cases, 121 tested were MM at codon 129 of the PRNP gene.

22 Countries with BSE in Native Cattle [yr first reported & approx. total cases reported to OIE thro’ Jan 2003] l UK 1986 (>182 581) [1443 in 2000; 1202 in ‘ 01; 755 in ‘ 02] l l l 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) l l l l l 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)

BSE Incidence per 106 Cows > 24 mo old

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) l l l 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 l l l l 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 l External challenge (probability that BSE agent entered a country) - Live cattle imports - Meat-and-bone meal imports l Internal Stability (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 l l 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 Confirmed at a higher level IV

Two EC GBR IV Countries United Kingdom l Portugal (mainland) l

31 Countries in EC GBR III l l l l Albania Austria Belgium Bulgaria Croatia Cyprus Czech Republic Denmark Finland France Germany Greece Hungary Ireland (Republic) Israel l l l Italy Japan Latvia Lithuania Luxembourg Malta Netherlands Poland Romania San Marino Slovak Republic Slovenia Spain Switzerland Turkey

Nine Countries in EC GBR II l Canada l Nigeria l Colombia l Pakistan l India l Sweden l Kenya l USA l Mauritius

17 Countries in EC GBR I l l l l l Argentina Australia Botswana Brazil Chile Costa Rica El Salvador Namibia New Zealand l l l l Nicaragua Norway Panama Paraguay Singapore Swaziland Uruguay Vanuatu

Predictive Record of EC GBR l l l l l 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) l l l 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) l 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)

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

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

Measures to protect humans from food-borne exposures to BSE agent (TSEAC Jan 2002 continued) Application of same measures to protect the human food chain to imported food and domestically produced food l Effective compliance with all above to be verified by - Inspections - Audits l

WHO Suggests Eight Questions from Consumers for National Authorities (“Understanding the BSE Threat” WHO 2002) 1) 2) 3) 4) 5) 6) 7) 8) 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 crosscontamination? 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 l l 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” l Monitor BSE and scrapie in annual active programs to include rapid [Pr. PTSE] tests. l 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. l l l 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 l 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. l Establish Reference Laboratories for TSE tests including rapid [Pr. PTSE] tests. l Carry out inspections and audits of EC Member States and “third” countries. l Reassess BSE status when OIE develops suitable procedures (proposes 5 categories instead of GBR IIV).

Regulation (EC) No 999/2001 (Annex) Five EC Proposed BSE categories 1) BSE-free: No BSE, no risk, all requirements met 7 yr, no MBM in feed 8 yr. 2) Provisionally BSE-free: No indigenous BSE [but history of risk] and compliant as for 1). 3) Similar to 2) but with a few indigenous cases of BSE 7 yr ago and compliant but not for 7 yr [&c] 4) Low BSE incidence: 1/106 but 100/106 animals 24 mo old. 5) 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 7 May 16 May 31 May Fertilizers Transport of animal products Transport of food 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) l European Commission http: //europa. eu. int/comm/food/fs/bse/index_en. html l France http: //www. afssa. fr/avis/index. asp? id l Switzerland http: //www. bvet. admin. ch/index_bse. html l UK Food Standards Agency http: //www. foodstandards. gov. uk/bse/facts l WHO http: //www. who. int/emc/diseases/bse/index. html