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From: TSS ()
© SEAC 2006 1 POSITION STATEMENT EVALUATION CRITERIA FOR ANTE MORTEM DIAGNOSTIC TESTS FOR SUBCLINICAL vCJD Issue 1. The Department of Health and the UK blood services requested SEAC’s advice on the scientific criteria by which ante mortem diagnostic tests for subclinical vCJD could be evaluated and validated1. Background 2. The development of an accurate and sensitive ante mortem blood test to identify asymptomatic individuals infected with vCJD could substantially reduce the potential for transmission of vCJD via blood transfusion and other medical interventions. It could also be valuable in confirming the diagnosis of clinical cases and monitoring the effect of potential therapies. In addition, such a test could provide an important tool to ascertain better the prevalence of vCJD infections. 3. The safety, quality and performance requirements for diagnostic tests for many infectious diseases are laid down in the In Vitro Diagnostic Medical Devices (IVD) Directive 98/79/EC. Tests included in Annex II List A of the Directive must comply with performance requirements set out in a Common Technical Specification (CTS) to receive a CE mark2. Currently, diagnostic tests for subclinical vCJD are not included in Annex IIA of the Directive and so a CTS with clear performance requirements for such tests has not yet been defined. Performance 4. The Committee on Microbiological Safety of Blood Tissue and Organs (MSBTO) considers that, ideally, tests for subclinical vCJD 1 The papers considered by SEAC are given at: http://www.seac.gov.uk/agenda/agen210906.htm 2 CE (Conformité Européenne) mark is a declaration by the manufacturer that a product meets all the necessary requirements of the relevant EU legislation. © SEAC 2006 2 should be highly sensitive and highly specific. Unless tests have extremely high specificity, they will generate a large number of false positive results with unacceptable cost and ethical consequences. Therefore, a reliable secondary test, to confirm reactive results in any initial screening test, would be required. Calculations to ascertain acceptable values for sensitivity and specificity of both the screening and confirmatory tests should be taken into account3. Regulatory position 5. Until diagnostic tests for subclinical vCJD are included in Annex IIA of the IVD Directive 98/79/EC, the CE mark must not be relied upon to indicate that a test is fit for purpose. Therefore, it is strongly recommended that ante mortem tests for subclinical vCJD are independently evaluated and validated using a clearly defined protocol prior to implementation. Prototype Tests 6. A number of prototype ante mortem blood tests for subclinical vCJD have been developed. Due to commercial sensitivities, availability of data for these tests is limited and the methodologies on which they are based are often incompletely specified. The available information suggests that many, if not all, of these tests are based on the detection of abnormal prion protein (PrPSc). 7. The relationship between the presence of PrPSc and vCJD infectivity is not well understood. It is important to emphasise that the presence of PrPSc is not always correlated with vCJD infectivity. However, as a better biomarker has not yet been identified, PrPSc is currently the most appropriate marker against which any assay should be targeted. Furthermore, it is possible that tests based on the detection of PrPSc will not identify all infected individuals and might falsely identify individuals as infective. As previously stated, calculations to ascertain what proportion of false positives and false negatives might be acceptable, are critical to defining test criteria. Evaluation and validation 8. Preliminary evaluation of the specificity and sensitivity of tests could be achieved by using human blood spiked with brain or 3 Eglin R and Bennett P (2003). Blood Screening for vCJD: Implications of test results (see SEAC papers at http://www.seac.gov.uk/agenda/agen210906.htm) © SEAC 2006 3 spleen homogenate from vCJD cases. However, spiked samples may not be representative of the form of infectivity naturally present in blood. Blood of animals infected with transmissible spongiform encephalopathy strains which, like vCJD are derived from the BSE strain may also provide a source of material to conduct preliminary evaluations. However, it is critical to note that the response of tests when applied to blood from animal models or spiked human blood, may not accurately reflect the response from tests when applied to the detection of vCJD infectivity in human blood. Therefore, the final evaluation of screening and confirmatory tests must include testing against blood from human vCJD cases. 9. Blood from clinical cases of vCJD may not provide an indication of the sensitivity of a test to correctly identify subclinically infected individuals. This is due to uncertainty in the levels of vCJD infectivity (and PrPSc) in blood during the incubation period of the disease. Individuals defined as ‘at risk of vCJD for public health purposes’ could provide a source of blood from potentially infected individuals at the preclinical stage of vCJD. Even so, such an evaluation would not inform on the ability of a test to detect infection from the point in the incubation period when blood becomes infectious. Such evaluation would require testing of blood collected from animal models at a number of time points through the incubation period, and extrapolation to humans. 10. As relevant human material is extremely difficult to obtain, it is essential that the quantity of materials required to validate tests is accurately determined prior to investigations starting. It is also important that an effective system to collect, manage and distribute these valuable materials is instituted and to ensure that the performance criteria that prototype tests must meet are clearly defined before such valuable materials are provided to evaluate and validate tests. Ethical Considerations 11. There are complex ethical issues associated with ante mortem testing for subclinical vCJD that have yet to be resolved4. These issues also relate to how many false positives and false negatives 4 The Chief Medical Officer (CMO) asked the Health Protection Agency (HPA) to host a seminar on the ethical and social aspects of testing for vCJD. This seminar produced a report with recommendations. At the request of the CMO, the HPA is currently undertaking a consultation exercise to determine the views of experts, health professionals and members of the public on the possible impact and implications of a test for vCJD. http://www.hpa.org.uk/infections/topics_az/cjd/consultation.htm © SEAC 2006 4 are acceptable and, hence, the test validation criteria. However, detailed consideration of these issues is not in SEAC’s remit. Conclusions 12. Until diagnostic tests for subclinical vCJD are included in Annex IIA of the IVD Directive 98/79/EC, the CE mark cannot be relied upon to indicate that a test has been properly and fully evaluated and validated. Therefore, tests should be independently and rigorously validated using a clearly defined protocol that includes testing of blood from vCJD cases. SEAC November 2006 http://www.seac.gov.uk/pdf/statement-vcjd.pdf PRODUCT ### PRODUCT ______________________________ END OF ENFORCEMENT REPORT FOR November 1, 2006 ### http://www.fda.gov/bbs/topics/enforce/2006/ENF00976.html ----- Original Message ----- Sent: Monday, October 09, 2006 2:48 PM IDENTIFIED HEALTH RISKS (SCENIHR) Opinion on The Safety of Human-derived Products with regard to Variant Creutzfeldt-Jakob Disease Adopted by the SCENIHR during the 11th plenary meeting of 11-12 May 2006 after public consultation Synthesis Report : http://ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr_vcjd_synth.pdf Stakeholder comments : http://ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr_vcjd_comments.zip EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL Directorate C - Public Health and Risk Assessment C7 - Risk assessment SCENIHR/003/05 The safety of human-derived products with regard to variant Creutzfeldt-Jakob disease _______________________________________________________________________ 2 TABLE OF CONTENTS EXECUTIVE SUMMARY ...............................................................................................4 1. BACKGROUND ..........................................................................................................7 2. TERMS OF REFERENCE ...........................................................................................8 3. SCIENTIFIC RATIONALE .........................................................................................9 3.1 Introduction .......................................................................................................9 3.2 Current status of knowledge on vCJD - overview..........................................10 3.2.1 The infectious agent ........................................................................................10 3.2.2 vCJD pathogenesis and the immune system ...................................................11 3.2.3 Distribution of infectivity and PrPSc in CJD ...................................................13 3.2.4 Evidence for the presence of vCJD infectivity in peripheral blood ................15 3.2.5 Conclusions .....................................................................................................15 3.3 Review of the TSE detection methods ............................................................15 3.3.1 Biochemical assay methods for the detection of PrPSc....................................16 3.3.2 Infectivity methods for the detection of TSE agents.......................................18 3.3.3 Surrogate markers of TSE disease...................................................................19 3.3.4 Other methods for the detection of TSE agents ..............................................19 3.3.5 Tests in development for blood .......................................................................20 3.3.6 Conclusions .....................................................................................................21 3.4 Evaluation of current epidemiological data.....................................................21 3.4.1 Surveillance systems and methodologies ........................................................21 3.4.2 Current variant CJD figures ............................................................................24 3.4.3 Modelling and predictions of vCJD figures ....................................................26 3.4.4 Epidemiological approaches to secondary transmission .................................29 3.4.5 Problems & possible deficiencies in current systems .....................................34 3.4.6 Conclusions .....................................................................................................34 3.5 Evaluation of prion decontamination procedures for surgical instruments.....35 3.5.1 Cleaning ...........................................................................................................35 3.5.2 Decontamination and sterilisation....................................................................36 3.5.3 Conclusions......................................................................................................38 3.6 Risk assessment on transmission of vCJD ......................................................38 3.6.1 Risk assessment for transmission of vCJD by blood or blood components ....39 3.6.2 Risk assessment on transmission by surgical instruments or invasive procedures ........................................................................................................................46 3.6.3 Risk assessment on vertical transmission .......................................................51 3.6.4 Risk assessment on transmission by transplantation of Umbilical Cord Stem Cells ................................................................................................................................53 3.6.5 Conclusions......................................................................................................53 SCENIHR/003/05 The safety of human-derived products with regard to variant Creutzfeldt-Jakob disease _______________________________________________________________________ 3 3.7 Evaluation of previous opinions of the SCMPMD on human product safety for vCJD transmission with regard to current scientific knowledge .....................................54 3.7.1 Opinion on Quality and Safety of Blood (Adopted by SCMPMD on 16 February 2000).................................................................................................................54 3.7.2 Opinion on update of the opinion given by SCMPMD on the risk quantification for CJD transmission via substances of human origin (Adopted by SCMPMD on 16 February 2000).....................................................................................55 3.7.3 Opinion on The Safety Of Human-Derived Products With Regard To TSE's (Adopted by SCMPMD on 18 January 2002)..................................................................56 4 COMMITTEE OPINION................................................................................60 5 MINORITY OPINION....................................................................................65 6 REFERENCES......................... 63 7 ACKNOWLEDGEMENTS ............................................................................80 GLOSSARY ....................................................................................................................81 SCENIHR/003/05 The safety of human-derived products with regard to variant Creutzfeldt-Jakob disease _______________________________________________________________________ 4 EXECUTIVE SUMMARY In 2004 two instances were reported indicating the possible transmission of variant Creutzfeldt-Jakob disease (vCJD) by blood transfusion. In February 2006 a third instance of vCJD infection by blood transfusion was reported. This prompted a review of the current state of knowledge and practice of vCJD infection in relation to the safety of blood and blood components, including the evaluation of previous scientific Opinions of the Scientific Committee for Medicinal Products and Medical Devices (SCMPMD). The general conclusions and recommendations of the previous Opinions on the safety of human derived products including blood and blood components are still valid. However, two aspects do need our attention: 1) the possibility of transmission of vCJD by blood and blood components, and 2), the presence of asymptomatic vCJD infected individuals in the population who may be responsible for secondary transmission of the disease by blood/blood components or surgery. While neither of the three transfusion-related vCJD infections reported is definitively proven to be caused by the preceding blood transfusion this is the most likely explanation. These three instances raise serious concern over the possibility of infection by blood transfusion (or through surgery and dental procedures) from asymptomatic preclinically or subclinically infected donors. Therefore, it is assumed that vCJD infectivity is likely to be present in human peripheral blood which is in accord with the results of recent work in experimental animals on transmission by transfusion. The present risk assessment of exposure to vCJD infectivity in whole blood and in blood components allows a rationale to define precautionary measures to reduce vCJD transmission within the human species by the intravenous or other routes. While all the clinical cases of vCJD so far have been homozygous for methionine, (MM) at codon 129 of the prion protein (PRNP) gene, one of the three reported transfusionrelated instances was heterozygous (MV). In addition, the results of the UK study evaluating anonymised appendix and tonsil surgical specimens, showed that vCJD infection might be more common than is suggested by the numbers of actual cases of vCJD to date. Two of the three positive samples could be evaluated for their genotype at codon 129 and were found to be of the VV genotype. It is therefore possible that following exposure to BSE, vCJD infectivity is present in a considerable number of individuals in the UK in an asymptomatic phase of the disease, including individuals with MV and VV genotypes. This poses an additional threat to the use of blood and other products of human origin as a potential source of secondary transmission. The potential transmission by blood raises concern, especially in view of the fact that routine screening with respect to vCJD is not (yet) possible. A possible iatrogenic transmission through surgical instruments used in invasive procedures also has important implications. Considerable advances in test methodologies for prion diseases have been made in recent years. However, no diagnostic system has yet emerged with the level of sensitivity and specificity required for routine screening of blood or urine. It is essential that confirmatory assays are available for any assay proposed for large scale screening of donated blood. In addition, prior to introduction into routine practice, such assays should be independently assessed and validated for their analytical performance. Validation of any new methodology should be mandatory prior to introduction, and it is recommended SCENIHR/003/05 The safety of human-derived products with regard to variant Creutzfeldt-Jakob disease _______________________________________________________________________ 5 that the EU adopts a procedure similar to that used for the BSE testing. For validation, carefully controlled vCJD reference materials should be used. The issue of false positives needs especially careful consideration. Even minute percentages of false positives may actually involve a large number of individuals if the tests are performed on a large scale in the EU population, with a varying "prevalence" of asymptomatic carriers. The ethical implications of testing and informing an individual of a positive test result, without providing any certainty as to the likelihood of progression to clinical disease, should not be considered lightly. Based on conservative assumptions made for the purposes of this risk assessment, there is a considerable risk that an asymptomatic donor infected with vCJD could cause infective material to be passed on to one or more recipients of blood or blood components. In the worst case scenario each therapeutic unit of blood from an asymptomatic infected donor could contain as much as 4500iv ID50. This amount of infectivity is deemed sufficient to cause transmission of the infection, with or without development of the disease. Considering that the donor population is much younger than the recipient population, with only a small overlap in age, preliminary data from one mathematical model indicate that blood transfusion alone will not be sufficient to maintain vCJD in the human population at large. Taking into account the eligible blood donor population, and using the data of the UK appendix-tonsils study, the number of donations and the percentage of the population actually donating blood, up to 1250 infected donations may occur per year. As donations are typically split between 3 recipients, 3750 new infections would occur each year in the UK as a result of these infected donations in the worst case scenario. Transfusion statistics show that in general only about 50 % of blood recipients survive more than 3 years. Accordingly half of the blood recipients will not live long enough after transfusion to develop vCJD. If all the surviving recipients do develop disease, 1875 new individuals per year could develop vCJD in the UK population The current decline in the onset of clinical vCJD in the UK and the general low number of cases in the older age groups who comprise the majority of blood recipients, indicate that this worst case scenario considerably overestimates transfusion-related vCJD disease development. There are several possible explanations for this. It is possible that most infections have a very long incubation period so that the individual dies before disease develops, or that infections in some groups such as the MV heterozygotes or VV homozygotes are not associated with blood infectivity, or that different genotypes do not transmit efficiently to each other even if the unit is infectious. There are analogies in animal models for these scenarios, and they reflect the difficulty in making realistic estimates of the number of cases expected from blood transfusion. Taking the lower limit of the confidence interval of the prevalence from the UK appendix-tonsils study and assuming that only ten percent of infectious donations actually transmit the infectious agent, the number of infected donations resulting would be 9 per year in contrast to the 1250 predicted by the worst case scenario. Independent of the method of calculation transmission by blood transfusion may occur. Based on current data, the frequency cannot be reliably estimated, but even in the UK it is probably low. The frequency is largely dependent on the number of asymptomatic vCJD infected individuals in the general population which is likely to differ from one Member State to another. SCENIHR/003/05 The safety of human-derived products with regard to variant Creutzfeldt-Jakob disease _______________________________________________________________________ 6 Epidemiological studies, similar to the UK appendix-tonsils study, are needed to collect data on the presence of infection (PrPRes) in the general population before estimations can be made on the possible frequency of contaminated blood donations in countries other than the UK. However, due to the rather low vCJD prevalence in other Member States there are considerable difficulties in the collection of such data, and alternative approaches for possible estimations of vCJD prevalence may therefore be used such as calculations based on BSE exposure. There is no evidence that individuals working in hospital settings have developed vCJD by virtue of their profession. Transmission of TSEs during surgical or dental procedures remains a concern, but to date there is no evidence that it has actually occurred in relation to vCJD. To minimize the risk of transmission of vCJD by surgical instruments cleaning and inactivation procedures are recommended based on the probability of the patient under investigation/treatment being infected with vCJD (or any other TSE). There are no proven instances of vertical transmission of any human prion disease. The available animal and human data are inadequate to allow firm conclusions concerning vertical transmission to be drawn. It is recommended that there is a follow-up for children that are born to mothers who had or developed clinical vCJD. There are no data indicating that breast milk transmits human prion disease. In the absence of evidence on vertical transmission in man, the risk posed by the use of cord blood which is of fetal origin can be considered to be negligible. However, contamination with maternal blood during collection remains a possibility. In conclusion, as long as there is a risk that infectious prion protein is present in blood and blood components, there will be a risk of transmission of vCJD disease by transfusion. Blood transfusion appears the most likely route for inter-human transmission of vCJD, although other routes of transmission should also be considered like surgery and organ or cell transplants.. The Committee does not consider that additional specific measures are needed to reduce the risk from vCJD infectivity in blood. In the UK and some other countries measures have already been taken including donor exclusion of blood transfusion recipients, leucodepletion, import of fresh frozen plasma, and reduction of amounts of plasma in blood components for transfusion. When there is a concern for spreading of vCJD by blood transfusion, donor exclusion of blood transfusion recipients is the appropriate measure. In addition, there are good practices to reduce any risk for transmission of infectious diseases such as optimal use of the transfusion to reduce the number of patients exposed, and optimal blood donation techniques and blood transfusion practices which minimize the number of blood donors to which an individual patient is exposed. The Committee recognises that it is important that Member States maintain the principle of regional blood supply structures, national surveillance systems and international information exchange at the EU level. snip...6 of 81 pages, full text ; RECALLS AND FIELD CORRECTIONS: BIOLOGICS -- CLASS II ______________________________ PRODUCT END OF ENFORCEMENT REPORT FOR SEPTEMBER 13, 2006 ### http://www.fda.gov/bbs/topics/enforce/2006/ENF00969.html PRODUCT END OF ENFORCEMENT REPORT FOR SEPTEMBER 6, 2006 ### http://www.fda.gov/bbs/topics/enforce/2006/ENF00968.html PRODUCT ______________________________ ______________________________ ______________________________ http://www.fda.gov/bbs/topics/enforce/2006/ENF00963.html ______________________________ ______________________________ ______________________________ ______________________________ ______________________________ ______________________________ ______________________________ ______________________________ ______________________________ ______________________________ END OF ENFORCEMENT REPORT FOR July 12, 2006 ### http://www.fda.gov/bbs/topics/enforce/2006/ENF00960.html PRODUCT ______________________________ PRODUCT ______________________________ ______________________________ _____________________________________ END OF ENFORCEMENT REPORT FOR July 5, 2006 ### http://www.fda.gov/bbs/topics/enforce/2006/ENF00959.html with new atypical TSE in the bovine, in the sheep, goat, and humans, and the fact that the new BASE TSE in cattle being very very similar to sporadic CJD, rather than the nvCJD, the fact that now science showing the TSE agent of the atypical cattle in Japan showing infectivity other than CNS tissue, the fact that the latest Texas mad cow and the recent Alabama mad cow both being of the atypical strain, it would seem prudent to include all human TSE in the blood ban, in my opinion. ... TSS Prion infections, blood and transfusions Adriano Aguzzi* and Markus Glatzel Prion infections lead to invariably fatal diseases of the CNS, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE), and scrapie in sheep. There have been hundreds of instances in which prions have been transmitted iatrogenically among humans, usually through neurosurgical procedures or administration of pituitary tissue extracts. Prions have not generally been regarded as bloodborne infectious agents, and case-control studies have failed to identify CJD in transfusion recipients. Previous understanding was, however, questioned by reports of prion infections in three recipients of blood donated by individuals who subsequently developed variant CJD. On reflection, hematogenic prion transmission does not come as a surprise, as involvement of extracerebral compartments such as lymphoid organs and skeletal muscle is common in most prion infections, and prions have been recovered from the blood of rodents and sheep. Novel diagnostic strategies, which might include the use of surrogate markers of prion infection, along with prion removal strategies, might help to control the risk of iatrogenic prion spread through blood transfusions. ... snip... the contrary, patients who are methionine/valine heterozygous at codon 129 of the PRNP gene are susceptible to infection with vCJD prions, which raises several important questions. Is the virulence of BSE prions enhanced when passaged from human to human, as opposed to the original bovine to human situation? Passaging experiments of scrapie infectivity between mice and hamsters indicate that this scenario is highly plausible.6 Even more importantly, can vCJD infection of heterozygous individuals establish a permanent subclinical carrier state? Although this situation might constitute a best-case scenario for the infected individuals, it could be disastrous from an epidemiological viewpoint, as it might lead to an unrecognized and possibly self-sustaining epidemic. ... snip... full text ; JUNE 2006 VOL 2 NO 6 AGUZZI AND GLATZEL NATURE CLINICAL PRACTICE NEUROLOGY 329 www.nature.com/clinicalpractice/neuro p.s. please note the 47 PENDING CASES to Sept. 2005 p.s. please note the 2005 Prion D. total 120(8) p.s. please note sporadic CJD 2002(1) 1=3 TYPE UNKNOWN??? p.s. please note 2004 prion disease (6) 6=7 TYPE FDA Fines American Red Cross $4.2 Million (BLOOD CJD) The U.S. Food and Drug Administration (FDA) announced today that the The fines stem from a recently completed FDA review of recalls conducted by Because receiving blood products always carries a degree of risk, it is Improvements in donor screening procedures and the use of a variety of new The amended consent decree requires ARC to: Establish clear lines of managerial control over a newly established While achieving a blood supply with zero risk of transmitting infectious Accurate and complete educational material for donors so that they can Blood donations are critically needed every day to save lives, and blood #### http://www.fda.gov/cber/talkpapers.htm#arc Red Cross fined $4.2 mln over blood safety By Lisa Richwine WASHINGTON (Reuters) - The U.S. government fined the American Red Cross $4.2 The fine, the largest ever levied by the Food and Drug Administration for a The agency said it had no evidence that any blood collected by the Red Cross "It is not acceptable that the quality systems failed in this way," Margaret The FDA said its investigation found that several Red Cross recalls of blood One way the Red Cross erred was by failing to ask donors about travel The problems involved 12,000 units of blood and blood components, FDA The latest fine was issued as part of a legally binding consent decree The 2003 deal revised a 1993 agreement that allowed the FDA to fine the Red The Red Cross said it would review the FDA's letter outlining its new "American Red Cross's senior management takes (the letter) seriously and is http://today.reuters.co.uk/news/articlenews.aspx?type=healthNews&storyID=2006-09-08T224834Z_01_N08403053_RTRIDST_0_HEALTH-REDCROSS-DC.XML http://today.reuters.co.uk/news/articlenews.aspx?type=healthNews&storyID=2006-09-08T224834Z_01_N08403053_RTRIDST_0_HEALTH-REDCROSS-DC.XML&pageNumber=1&imageid=&cap=&sz=13&WTModLoc=NewsArt-C1-ArticlePage1 Terry S. Singeltary Sr.
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