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Presentation layout 1. 2. Introductory remarks New Infectious Disease Paradigm Prion-related diseases: • • • 3. TSEs Prions Human prion disease hypothesis EU medico-scientific TSE Epidemiology • • 4. • Human Animal EU TSE Legislative Framework Food and feed products William P. Charteris • chronology of EU consumer health protection measures (1988-2005) • • key EU TSE protection measures The Consultant’s Consultant™ EU TSE Legislative Road Map • • 6. 7. www.billcharteris.com summary of EU TSE protection measures Blood products • 5. and regulatory issues, problems, and recommendations Proposed changes to EU TSE protection measures (2005-2014) Nov. 7th, 2005. Personal recommendations Concluding remarks Addendum Introductory remarks 1. BSE epidemic (1986-2014) • • • • • 2. 1.6 million infected animals entered the human food chain huge number of animals destroyed EU, CH, JP, CA, USA total estimated losses: €100 billion significant decline in disease incidence since 2002 nvCJD epidemic (1996-2010) • • • • 3. Table 2: Probable and definitive mortality from nvCJD in the UK (as of October 5 2005) not more than 500 fatalities; < 200 lives more likely UK, IE, FR, PT compensation: £125,000 per victim significant decline in disease incidence since 2000 Year Risk assessment and management Table 1: Prevalence of BSE in the EU and UK • bovine • • • Parameter ovine caprine cervid Incidence of BSE [2004] Reduction since 2002 Incidence of BSE in healthy slaughtered animals [2004] a new infectious disease paradigm Reduction since 2003 Incidence ofBSE in high risk animals [2004] in the face of incomplete knowledge Reduction since 2003 4. Risk communication undermined public confidence Source: EU TSE Annual Report 2004 Number of cases EU25 UK 865 40% 166 39% 520 35% 343 30% 151 43% 243 49% nvCJD sCJD iCJD fCJD GSS Total 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 3 10 10 18 15 28 20 17 18 9 3 28 32 45 37 53 35 40 60 63 62 50 58 72 77 52 41 5 1 2 4 1 4 4 6 3 6 1 4 0 5 2 1 0 3 5 3 4 2 2 4 3 2 2 3 4 4 3 2 0 0 1 2 3 3 4 1 2 0 1 2 1 2 1 1 33 36 53 46 61 47 60 81 89 85 82 87 94 106 67 48 All 151 805 49 46 24 1,075 Source: UK Department of Health The New Infectious Disease Paradigm Transmissible spongiform encephalopathies sheep 1. Characteristics • • • • 2. very rare, uniformly fatal neurodegenerative diseases Table 3: Human and animal prion disease long incubation period multi-focal neuropathology Mode of transmission Prion disease toxic gain of function of an aberrant form of a constitutive protein Human Animal Classification of prion-related diseases • • • 3. infectious infectious sporadic genetic villi genetic fCJD GSS FFI sporadic sCJD Pathogenesis • • • 4. penetration and peripheral replication translocation and neuroinvasion neurodegeneration Transmissibility barriers (R/M) • • inter-species transmission barrier intra-species transmission barrier • strain transmission barrier • adaptation nvCJD iCJD kuru BSE Scrapie cow TME CWD CJD - Creutzfeldt-Jakob human nv - new variant i - iatrogenic f - familial s - sporadic GSS - Gerstmann-Straüssler-Scheinker Syndrome FFI - Fatal Familiar Insomnia BSE – bovine spongiform encephalopathy TME – transmissible mink encephalopathy CWD – chronic wasting disease The New Infectious Disease Paradigm Prions 1. Structural types • native or constitutive [PrPc] • non-toxic proteins/peptides characterized by: • foreign or pathogenic [PrPres] • amyloid proteins/peptides characterized by: • • • • • 2. (b) high β sheet content (d) birefringence on Congo Red staining toxic amyloid, inactive amyloid, active amyloid, and self-activating enzyme stable interchangeable conformers of each another [PrPc + PrPres -> 2 PrPres] PrPc is a ubiquitously expressed, GPI-anchored membrane bound glycoprotein theTable precise nature of its physiological role remains a mystery proteins and peptides 4: Examples of human amyloid it has dual neurological and immunological functions it is likely that PrPc represents a new type of pattern recognition receptor Protein Disorder its likely evolutionary origin - a horizontally transferred gene from an early RNA virus Genetics Aβ peptides Alzheimer’s disease chromosomally encoded: Transthyretin Senile systemic amyloidosis • Serum PrPc is encoded by chromosome 20 at 20pter-p12 amyloid A PRNP on human Secondary systemic amyloidosis • SNP polymorphism at codon 129 on human PRNP (infections and chronic inflammatory conditions) • MV heterozygote individuals have increased resistance to disease • MM homozygotes individuals have increased susceptibility to disease Amylin (IAPP) Type II diabetes Transmissibility to humans α -synuclein Parkinson’s disease • bovines: confirmed Superoxide dismutase Amyotrophic amyloidosis • the mean nvCJD incubation period following consumption of an infectious dose of BSE-infected β 2-microglobulin beef by MM homozygote is 16.7Hemodialysis-related years (95% CI, 8–30 years) amyloidosis Huntingtin Huntington’s disease • sheep, goats, deer, etc.: not confirmed PrP Transmissible spongiform encephalopathies Ig light chain Primary systemic amyloidosis • 4. (a) filamentous morphology (c) relative protease resistance (b) relative protease sensitivity Function • • • • • 3. (a) high a-helix content The New Infectious Disease Paradigm Human Prion Disease Hypothesis 1. Background • • 2. The cause of the original case or cases of BSE remains an enigma Sheep scrapie or a previously undetected sporadic form of BSE have long been considered as candidates, but no convincing evidence to support these proposals has come to light New Theory • 3. A new theory has been presented, with three related hypotheses: • that BSE was acquired from a human TSE • that the route of infection was oral, through animal feed containing imported mammalian raw materials contaminated with human remains • that the origin was the Indian subcontinent, from which large amounts of mammalian material were imported during the relevant time period. Human remains are known to be incorporated into meal made locally, and may still be entering exported material! Research requirements • Further investigations are needed regarding: • the sources of animal by-products used in animal feed manufacture • the transmissibility of human TSEs to cattle Colchester, A. C., and N. T. Colchester. 2005. The origin of bovine spongiform encephalopathy: the human prion disease hypothesis. Lancet 366:856-61. TSE Epidemiology Human Characteristics of nvCJD epidemic • Figure 1: UK nvCJD mortality (1990 – October 5 2005) Zoonosis with age-dependent susceptibility • • • • • dietary exposure individual susceptibility (genetics, etc.) Mean incubation period is 15 years Mean age at death is 29 years Started - 1994; Peaked - 2001; End - 2010 • • • exposure before 1986 exposure after 1989 SBO ban [90% effective] An epidemic of relatively moderate size • • 30 not more than 500 lives; < 200 lives more likely UK, FR, IE, IT, USA, CA affected 25 UK nvCJD mortality 1. 20 15 Table 5: Summary of nvCJD cases in the UK (1990 – October 5 2005) 2. Unresolved issues Details • StatusDifferential diagnosis at autopsy • Alive • Number 10 diminishing number of referrals Number of definite/probable nvCJD cases still alive 6 Evolution of epidemic in homozygous individuals 5 ban bimodal distribution to MRM not included in the 1989 SBO Deaths from due definite nvCJD (confirmed) from in probable nvCJDindividuals (without neuropathology confirmation) EvolutionDeaths of epidemic heterozygous Deaths from probable nvCJD (neuropathology confirmation pending) • 60% of the population • • All 0 • Secondary transmission (blood, bone, medical devices, etc.) Total number of probable and confirmed nvCJD cases (alive and low level endemicity in humans and animals deceased) Source: UK Department of Health 2005 108 42 1 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 • Deceased Year Source: www.cjd.ed.ac.uk/figures.htm 157 Animal 1. Characteristics of bovine epidemic • Unknown cause • • • • dietary exposure individual susceptibility (genetics, etc.) Mean incubation period is 5 years Started -1986; Peak - 1992; End - 2014 • • • 30,000 20,000 10,000 0 Year exposure before 1986 exposure after 1989 SBO ban [90% effective] Source: EC TSE Annual Report 2004 An epidemic of large size • • • • 40,000 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 TSE Epidemiology BSE positive cases Figure 2: Evolution of BSE in the UK 188,809,000 infected bovines [EU25: 1988-2004] 1.6 million entered the human food chain Figure 3: Evolution of BSE in other countries affected number of risk animals destroyed total estimated losses: 100 billion euro 350 Sheep • • • Goats • • 3. 2,332 TSE cases a population of 89,838,000 [EU25: 2004] 250 CY (52%), FR (20%), UK (14%) 200 Inter-species transmission [1998-2004] • • FR DE 398 TSE cases in a population of 12,370,000 [EU25: 2004] 150 CY (89%), FR (7%), GR (1%) Unresolved issues • IE CH JP 100 50 bovine->ovine: not shown by bio-assay [3,506 tests] 0 bovine->caprine: 1 confirmed FR case by bio-assay [57 tests] 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 • BSE-positive cases 300 Characteristics of ovine and caprine ‘epidemics’ 2. Year Source: EC TSE Annual Report 2004 EU TSE Regulatory Framework Food & Feed Products 1. Background Table 6: Selected chronology of EU consumer health protection measures (1989 – 2005) Year Regulatory Measure 1989 1990 Restrictions on the dispatch of certain live cattle from the UK Compulsory notification of BSE Restrictions on the dispatch of certain bovine tissues and organs from the UK Restrictions on the dispatch of bovine embryos from the UK Ban on the use of mammalian-derived proteins for feeding ruminants Rendering systems for processing ruminant waste into MBM (inactivation of BSE agents) Total ban on dispatch of live cattle and all cattle products from the UK (UK embargo) Eradication programmes for BSE in the UK and Portugal Prohibition of the use of SRM (mainly brain, eyes and spinal cord) Restrictions on trade in MBM Epidemiological surveillance for all animal TSEs Total ban on dispatch of live cattle and all cattle products from Portugal (Portugal embargo) Conditions for the production of MBM and tallow (Repeals D 96/449/EC) Temporary ban on use of MBM Prohibition of the use of dead animals in the production of animal feed Prevention, control and eradication of certain TSE Establishment of breeding programmes for resistance to TSEs in sheep Requirements for the import of cervid products from Canada and the United States Systematic BSE-scrapie discriminatory tests for all confirmed TSE cases in small ruminants Increased TSE monitoring in goats Prohibition of products derived from bovine animals born or reared in the UK before 1 August 1996 1992 1994 1996 1997 1998 1999 2000 2001 2003 2004 2005 EU TSE Regulatory Framework Food & Feed Products 2. Protective measures Table 7: EU TSE Protective Measures Measure Details Country restrictions DEC 98/256 (UK embargo Decision) 1996-2005: UK Over-Thirty-Months (OTM) Rule 2006: permanent exclusion of cattle born before 1 August 1996 from the food and feed chain \ some exceptions like the use of fish meal for non-ruminants these tissues must be removed from the food and feed chains \ prohibition for use in food and feed such as tallow, gelatine, collagen, and dicalcium phosphate 1994-2000: partial ban on the feeding of mammalian MBM to cattle, sheep and goats was introduced in July 1994 2001: total EU wide ban on the use of processed animal protein in feeds for any food animals Joint Research Centre, Ispra, Italy culling of epidemiologically linked ‘birth’ and ‘feed’ cohorts to bovine TSE cases whole or partial (sensitive genotypes) culling if TSE is detected in sheep, including atypical cases whole herd culling of goats if TSE is detected a minimal sheep breeding programme became mandatory for flocks of high genetic merit on 1 April 2005 Country categorisation according to BSE risk has as its objective the definition of trade rules to protect animal and public health in importing countries. The conditions for such trade are already laid down in the current recommendations of the Terrestrial Animal Health Code of the World Organisation for Animal Health (OIE Code) bovine passive monitoring up to July 2001; active monitoring thereafter \ all risk animals over 24 months of age and all healthy slaughtered animals above 30 months of age (≈ 10 million p. passive monitoring up to 2002; active monitoring thereafter \ risk animals and healthy slaughtered animals over 18 months of age \\ minimum of 10,000 sheep and 10,000 goats per Member State extended monitoring of all healthy slaughtered goats since 2005 Specified Risk Material Feed ban Prion inactivation research Disease eradication Breeding for resistance Country categorisation and trade rules Monitoring & Age of Testing Source: COM (2005) 0322 FINAL EU TSE Regulatory Framework Blood and blood products 1. Background • high therapeutic value but communicable disease transmission risks to patients Table 8: Key EU Blood Regulatory Measures Year Regulatory document 1998 2001 REC 1998/10 ohe use of human red blood cells for the preparation of oxygen-carrying substances Parliamentary questions - Written question E-0096/01 BSE: blood donations REC 2001/4 on the prevention of the possible transmission of variant Creutzfeldt-Jakob Disease Parliamentary questions - Written question E-1079/01 Commercial action for the storage of umbilical cord blood for obtaining stem cells DIR 2002/98 on the quality and safety of blood and blood components Parliamentary questions - Written question P-0590/02 Europeanisation of Italian law 107/90 on the production of blood derivatives REC 2002\11 on the hospital's and clinician's role in the optimal use of blood and blood products Council of Europe Guide to the preparation, use and quality assurance of blood components Draft Technical Requirements for blood and blood components Opinion of the Scientific Committee on Medicinal Products and Medical Devices on the impact of REC 2003\11 on the introduction of pathogen inactivation procedures for blood components Precautionary measures against WNV transmission by blood Precautionary measures against nvCJD transmission by blood DIR 2004/33 on certain technical requirements for blood and blood components Dir 2005 0061 on blood traceability + adverse events Dir 2005 0062 on quality system for blood establishments 2002 2003 2004 2005 EU TSE Regulatory Framework Blood and blood products 2. Protective measures • DIR 2004/0033 on technical requirements for the collection, testing, processing, storage, and distribution of human blood and blood components • • • • • • 3. permanent deferral criteria for persons who have a family history which places them at risk of developing a TSE, or persons who have received a corneal or dura mater graft, or who have been treated with medicines made from pituitary glands; temporary deferral criteria for blood donors who have inter alia received a blood transfusion, a tissue or cell transplant of human origin, or undergone major surgery; other deferral for particular epidemiological situations. These deferrals are to be notified by the competent authority to the Commission with a view to Community Action. DIR 2002/0098 on quality and safety standards for blood and blood components DIR 2005/0061 on blood traceability + adverse events DIR 2005/0062 on quality system for blood establishments Additional measures • other patient groups ‘potentially at-risk of nvCJD for public health purposes’: • • • • certain patients who have been operated on with instruments previously used for healthcare interventions on a patient with nvCJD recipients of blood from donors who later developed nvCJD patients who have been treated with plasma products that may have been contaminated with nvCJD infection new patient group (UK and Ireland): • ‘donors to nvCJD cases’ (about 100) [UK and Ireland only] EU TSE Regulatory Road Map 2005 to 2014 1. Background • • 2. Declining nvCJD and BSE epidemics Emerging risks incl. avian influenza, SARS, etc. Strategic goals Table 9: Strategic goals of the EU TSE Regulatory Road Map (2005-2014) Strategic goal 1 2 3 4 5 6 7 1 2 Details Short to medium term – 2005 to 2009 To ensure and maintain the current level of consumer protection by continuing to assure the safe removal of SRM but modify list/age based on new & evolving scientific opinion A relaxation of certain measures of the current total feed ban when certain conditions are met To reduce the numbers of tests of bovine animals and at the same time continue to measure the effectiveness of the measures in place with a better targeting of the surveillance activity Simplification of the categorisation criteria and conclusion of the categorisation of the countries before 1 July 2007 Review and relaxation of the eradication measures for small ruminants taking into account the new diagnostic tools available but ensuring the current level of consumer protection To stop the immediate culling of the bovine cohort To discuss the lifting of the additional restrictions on exports of beef and beef products from the UK if the preset conditions are complied with Short to medium term – 2009 to 2014 To modify measures in line with current technology and new evolving scientific knowledge Scenario analysis EU TSE Regulatory Road Map Personal recommendations 1. Risk assessment • subpopulation susceptibility to nvCJD heterozygous individuals prion transmissibility • human to animal (bovine, ovine, caprine, etc.) • animal to animal (bovine-caprine, etc.) • animal to human (cervids, etc.) age-dependent susceptibility to nvCJD • maturation of gastrointestinal epithelial barrier function • • • 2. Risk management • true nature of the prion-related diseases a genetic/somatic disorder more like cancer than an infectious disease appropriateness and efficacy of protective measures • surveillance, quarantine, and slaughter? reinforce transmissibility barriers • absolute prohibition on at-risk blood, tissue, and organs donors • absolute prohibition on occult cannibalism • temporary ban on inter-species recycling • • • 3. Risk communication • • • 4. true nature and impact of both epidemics likelihood of associated epidemics memorialize nvCJD victims Global assistance • proactive provision of risk-based support services Concluding remarks 1. Global risk and the global need for action 2. there is a global risk of TSE due to trade in live animals and certain animal-tissue containing products (incl. meat and meat products and animal feed) it is essential that countries should not wait until their first case of TSE before acting Risk assessment 3. countries without known TSE cases must conduct risk assessments and may require surveillance systems for both human and animal TSEs the global risk assessment must include information about global trade practices with the aim of identifying potentially high risk activities there are some hypothesized risks in trade in live animals, meat and meat products, and animal feed Risk management 4. policies to minimize human exposure to TSE have been introduced (and evaluated) in many countries extensive international experience has accrued regarding the most significant measures to be adopted to reduce the risk of TSE Risk communication one of the largest problems has been the difficulties in communicating risks in the face of incomplete knowledge the process of development of public policy through iterative processes has undermined public confidence. Addendum 1. Presentation details 2. Other important presentation details 3. prepared using MS PowerPoint 2003 with custom animation settings on each slide speaker notes are available for each slide a narrated version of the presentation has been prepared with Articulate Presenter the narrated presentation can be viewed on-line at the following URL: www.imperialconsulting.net/ass01for705c1x/index.html Assignment details: ASSIGNMENT 1 FOR 705C1X Prepare a 15 minute presentation comprising 12 PowerPoint slides (excluding references) and speaker notes (100 words max.) on a regulatory issue of current concern. The presentation should be directed at the management board of your company or the management group of your ministry or equivalent. It should concisely and precisely lay out the main issues and problems and make recommendations for action. Prion-related diseases: Issues, problems, and recommendations Submitted by William P. Charteris [Student Registration Number 32491904] PG Dip Eur Food Regul Aff DL