2. MEDICAL DEVICES ADVISORY COMMITTEE MEETING OF THE GENERAL HOSPITAL AND PERSONAL USE DEVICES PANEL Transmissible Spongiform Encephalopathy (TSE) September 27, 2005 Infection Control Devices Branch Division of Anesthesiology, General Hospital, Infection Control and Dental Devices Center for Devices and Radiological Health

3. September 27, 2005HHS/FDA/CDRH3 Transmissible Spongiform Encephalopathy Introduction Sheila A. Murphey, MD Branch Chief Infection Control Devices Branch Division of Anesthesiology, General Hospital, Infection Control and Dental Devices Center for Devices and Radiological Health

4. September 27, 2005HHS/FDA/CDRH4 General Hospital and Personal Use Devices Panel The Advisory Panel is asked to address the scientific issues surrounding the evaluation of products/processes intended to reduce the bioburden of the Creutzfeldt-Jakob transmissible agent on contaminated surgical instruments. The Advisory Panel is asked to address the scientific issues surrounding the evaluation of products/processes intended to reduce the bioburden of the Creutzfeldt-Jakob transmissible agent on contaminated surgical instruments.

5. September 27, 2005HHS/FDA/CDRH5 General Hospital and Personal Use Devices Panel In July 2003, DAGID asked the Transmissible Spongiform Encephalopathies Advisory Committee (TSEAC) to address the issue of reprocessing medical devices contaminated or potentially contaminated by TSE agents. In July 2003, DAGID asked the Transmissible Spongiform Encephalopathies Advisory Committee (TSEAC) to address the issue of reprocessing medical devices contaminated or potentially contaminated by TSE agents.

6. September 27, 2005HHS/FDA/CDRH6 General Hospital and personal Use Devices Panel The questions on instrument decontamination asked of TSEAC were general and received general responses. The questions on instrument decontamination asked of TSEAC were general and received general responses. TSEAC pointed out that little of the experimental literature on TSE inactivation is directly applicable to hospital settings. TSEAC pointed out that little of the experimental literature on TSE inactivation is directly applicable to hospital settings.

7. September 27, 2005HHS/FDA/CDRH7 General Hospital and Personal Use Devices Panel TSEAC stated that “there is no threshold value below which exposure to a TSE agent should be considered safe. TSEAC stated that “there is no threshold value below which exposure to a TSE agent should be considered safe. TSEAC stated that “use of existing methods cannot assure complete removal of TSE agents from all materials under all circumstances”. TSEAC stated that “use of existing methods cannot assure complete removal of TSE agents from all materials under all circumstances”.

8. September 27, 2005HHS/FDA/CDRH8 General Hospital and Personal Use Devices Panel The Division of Anesthesiology, General Hospital, Infection Control and Dental Devices (DAGID) believes that it needs more guidance on the issues of TSE contamination of surgical instruments The Division of Anesthesiology, General Hospital, Infection Control and Dental Devices (DAGID) believes that it needs more guidance on the issues of TSE contamination of surgical instruments

9. September 27, 2005HHS/FDA/CDRH9 General Hospital and Personal Use Devices Panel The number of scientific articles addressing the reduction/removal of TSE from instrument proxies is increasing The number of scientific articles addressing the reduction/removal of TSE from instrument proxies is increasing Public interest in and concern about variant Creutzfeldt-Jakob disease and its potential for causing infections in the US is increasing Public interest in and concern about variant Creutzfeldt-Jakob disease and its potential for causing infections in the US is increasing

10. September 27, 2005HHS/FDA/CDRH10 General Hospital and Personal Use Devices Panel DAGID believes that it should prepare for the possibility that products or processes intended to reduce TSE infectivity on surgical instruments will be submitted to FDA for premarket evaluation. DAGID believes that it should prepare for the possibility that products or processes intended to reduce TSE infectivity on surgical instruments will be submitted to FDA for premarket evaluation.

11. September 27, 2005HHS/FDA/CDRH11 General Hospital and Personal Use Devices Panel Presentations by FDA Sheila A. Murphey, MD Elaine S. Mayhall, PhD Estelle Russek-Cohen, PhD Ronald Brown

12. September 27, 2005HHS/FDA/CDRH12 General Hospital and Personal Use Devices Panel Guest Speaker Allan Hidderley Senior Medical Device Specialist Medicines and Healthcare Products Regulatory Agency (Devices) Device Technology and Safety-Biologics and Implants United Kingdom

13. September 27, 2005HHS/FDA/CDRH13

14. September 27, 2005HHS/FDA/CDRH14 Transmissible Spongiform Encephalopathy Introduction Elaine Schalk Mayhall, Ph.D. Infection Control Devices Branch Division of Anesthesiology, General Hospital, Infection Control and Dental Devices Center for Devices and Radiological Health

15. September 27, 2005HHS/FDA/CDRH15 Transmissible Spongiform Encephalopathy Transmissible spongiform encephalopathies (TSE) are rare, progressive neurodegenerative diseases which affect both humans and animals. Transmissible spongiform encephalopathies (TSE) are rare, progressive neurodegenerative diseases which affect both humans and animals. TSEs result from the accumulation of the abnormal isoform of a normal host cell protein which causes progressive neuronal dysfunction. TSEs result from the accumulation of the abnormal isoform of a normal host cell protein which causes progressive neuronal dysfunction.

16. September 27, 2005HHS/FDA/CDRH16 Human Transmissible Spongiform Encephalopathies Idiopathic - sporadic Creutzfeldt-Jakob Disease (CJD) - sporadic fatal familial insomnia Transmissible by Ingestion - variant CJD (from BSE) - Kuru Inherited - familial CJD - familial fatal insomnia - Gerstmann-Straussler-Scheinker Syndrome

17. September 27, 2005HHS/FDA/CDRH17 Animal Transmissible Spongiform Encephalopathies ScrapieSheep Bovine Spongiform Encephalopathy (BSE) Cattle (? from Scrapie) Transmissible Mink Encephalopathy Mink (? from Scrapie) Feline Spongiform Encephalopathy Cats (from BSE) Exotic Ungulate Encephalopathy Kudu, oryx, etc. (from BSE) Chronic Wasting Disease Deer and Elk

18. September 27, 2005HHS/FDA/CDRH18 Pathogenesis of Human Transmissible Spongiform Encephalopathy PrP c Prion protein (cellular) - also called PrP sen Encoded by PRNP Encoded by PRNP Normal protein isoform, expressed on the surface of neurons, glial cells, other cells Normal protein isoform, expressed on the surface of neurons, glial cells, other cells Function uncertain Function uncertain Prion stands for proteinaceous infectious particle

19. September 27, 2005HHS/FDA/CDRH19 Pathogenesis of Human TSE PrP res (PrP sc ) Abnormal isoform of the normal prion protein, PrP Abnormal isoform of the normal prion protein, PrP Induces the conversion of PrP c to PrP res Induces the conversion of PrP c to PrP res Accumulation of the abnormal isoform PrP res causes fatal neurodegenerative disease with a long incubation period Accumulation of the abnormal isoform PrP res causes fatal neurodegenerative disease with a long incubation period

20. September 27, 2005HHS/FDA/CDRH20 Pathogenesis of Human TSE PrP sen PrP res Monomer Oligomer or Polymer Sensitive to proteinase K Resistant to proteinase K Cell surface Vesicles Rapid synthesis and degradation Slow synthesis and degradation

21. September 27, 2005HHS/FDA/CDRH21 Pathogenesis of Human TSE Conversion of PrP sen to PrP res Acquisition of abnormal isoform Acquisition of abnormal isoform “Sporadic” (Idiopathic) (?somatic mutation) “Sporadic” (Idiopathic) (?somatic mutation) Ingestion Ingestion Iatrogenic transmission Iatrogenic transmission Inheritance of an abnormal isoform at least 30 mutations described Inheritance of an abnormal isoform at least 30 mutations described

22. September 27, 2005HHS/FDA/CDRH22 Transmission of Human TSE When PrP res is present, it can be transmitted to another host When PrP res is present, it can be transmitted to another host Transmission requires prion transfer, usually in tissue. Transmission requires prion transfer, usually in tissue. While central nervous system (CNS) tissue is the most effective vehicle, other tissues can also transfer prions While central nervous system (CNS) tissue is the most effective vehicle, other tissues can also transfer prions Efficiency of transmission is dose-related Efficiency of transmission is dose-related

23. September 27, 2005HHS/FDA/CDRH23 Transmission of TSE Risk of TSE transmission will be determined by Availability of a TSE source Availability of a TSE source Likely frequency of a “transmissible” encounter with a TSE source Likely frequency of a “transmissible” encounter with a TSE source Effective TSE “dose” Effective TSE “dose” Larger doses are more efficient in transmission Larger doses are more efficient in transmission

24. September 27, 2005HHS/FDA/CDRH24 Iatrogenic Transmission of Creutzfeldt-Jakob disease Source #Incubation period Neurosurgery 517 months (12-28 m) EEG Electrodes 2 16-20 months Cornea Transplant 3 16-320 months Dura mater grafts 1146 yrs (1.5 – 18 yrs) Growth Hormone 13912 yrs ( 5-30 yrs) Gonadotropin 413 yrs ( 12-16 yrs) P Brown et al, Neurology 2000, 55:1075-1081

25. September 27, 2005HHS/FDA/CDRH25 Iatrogenic Transmission of CJD by Contaminated Surgical Instruments All 7 reported cases of CJD transmission by contaminated surgical instruments/EEG electrodes occurred between 1954 and 1980 All 7 reported cases of CJD transmission by contaminated surgical instruments/EEG electrodes occurred between 1954 and 1980 All 7 reported cases of CJD transmission by contaminated surgical instruments/EEG electrodes occurred in Europe (UK 4, Switzerland 2, France 1) All 7 reported cases of CJD transmission by contaminated surgical instruments/EEG electrodes occurred in Europe (UK 4, Switzerland 2, France 1)

26. September 27, 2005HHS/FDA/CDRH26 Preventing Iatrogenic TSE Transmission by Contaminated Instruments Human forms of TSE can be transmitted Human forms of TSE can be transmitted Transmission by materials and instruments contaminated by CNS tissue from CJD patients has occurred Transmission by materials and instruments contaminated by CNS tissue from CJD patients has occurred CJD patients are not always promptly diagnosed in the early stages of disease CJD patients are not always promptly diagnosed in the early stages of disease

27. September 27, 2005HHS/FDA/CDRH27 Preventing Iatrogenic TSE Transmission by Contaminated Instruments Currently Recommended Clinical Practice Currently Recommended Clinical Practice Precautions to prevent the transmission of TSE by contaminated surgical instruments should be taken for invasive CNS procedures in patients with dementia of uncertain origin and patients known or suspected of having TSE. Precautions to prevent the transmission of TSE by contaminated surgical instruments should be taken for invasive CNS procedures in patients with dementia of uncertain origin and patients known or suspected of having TSE. Precautions to prevent instrument transmission should also be taken for extraneural procedures although the risk of transmission is lower. Precautions to prevent instrument transmission should also be taken for extraneural procedures although the risk of transmission is lower.

28. September 27, 2005HHS/FDA/CDRH28 Preventing Iatrogenic TSE Transmission by Contaminated Instruments Currently Recommended Clinical Practice Surgical instruments may be discarded Surgical instruments may be discarded Surgical instruments may be quarantined until a diagnosis is confirmed Surgical instruments may be quarantined until a diagnosis is confirmed Surgical instruments may be treated with processes shown to have some in-vivo effect in reducing TSE transmission and recommended by CDC Surgical instruments may be treated with processes shown to have some in-vivo effect in reducing TSE transmission and recommended by CDC

29. September 27, 2005HHS/FDA/CDRH29 Preventing Iatrogenic TSE Transmission by Contaminated Surgical Instruments Studies at the National Institutes of Health have identified several methods of instrument treatment which reduce TSE transmission. Studies at the National Institutes of Health have identified several methods of instrument treatment which reduce TSE transmission. These have been recommended for clinical consideration by the CDC and other authorities. These have been recommended for clinical consideration by the CDC and other authorities.

30. September 27, 2005HHS/FDA/CDRH30 Preventing Iatrogenic TSE Transmission by Contaminated Instruments Currently Recommended Clinical Practice Prevacuum steam sterilization at 134 0 C for 18 min Prevacuum steam sterilization at 134 0 C for 18 min Gravity steam sterilization at 121 0 C for 1 hr Gravity steam sterilization at 121 0 C for 1 hr Immersion in 1 N NaOH for 1 hr Immersion in 1 N NaOH for 1 hr

31. September 27, 2005HHS/FDA/CDRH31 Preventing Iatrogenic TSE Transmission by Contaminated Instruments NaOH immersion and TSE sterilizer cycles have been used together NaOH immersion and TSE sterilizer cycles have been used together Sodium hypochlorite immersion has been recommended by some authorities Sodium hypochlorite immersion has been recommended by some authorities Currently recommended decontamination procedures are corrosive and unsuitable for heat-sensitive materials Currently recommended decontamination procedures are corrosive and unsuitable for heat-sensitive materials

32. September 27, 2005HHS/FDA/CDRH32 Preventing Iatrogenic TSE Transmission by Contaminated Instruments Currently recommended procedures for treating CJD-contaminated surgical instruments have not been systematically studied for clinical efficacy Currently recommended procedures for treating CJD-contaminated surgical instruments have not been systematically studied for clinical efficacy

33. September 27, 2005HHS/FDA/CDRH33 Preventing Iatrogenic TSE Transmission by Contaminated Instruments Iatrogenic transmission of CJD by CJD- contaminated surgical instruments has not been reported since 1980 Iatrogenic transmission of CJD by CJD- contaminated surgical instruments has not been reported since 1980 Small epidemiologic studies of risk factors for CJD have not consistently shown any statistically significant association between surgery and CJD Small epidemiologic studies of risk factors for CJD have not consistently shown any statistically significant association between surgery and CJD

34. September 27, 2005HHS/FDA/CDRH34 Preventing Iatrogenic TSE Transmission by Contaminated Instruments Exposures of patients to instruments used in invasive CNS procedures on patients with unrecognized CJD have been reported. Exposures of patients to instruments used in invasive CNS procedures on patients with unrecognized CJD have been reported. No cases of iatrogenic CJD resulting from these exposures have yet been reported. No cases of iatrogenic CJD resulting from these exposures have yet been reported.

35. September 27, 2005HHS/FDA/CDRH35 Transmission of TSE Availability of a TSE Source in the US “Sporadic” CJD is the most common TSE in the US “Sporadic” CJD is the most common TSE in the US Average annual US death rate from CJD is 0.95 per million persons Average annual US death rate from CJD is 0.95 per million persons vCJD has been described only once in the US in a recent UK emigrant vCJD has been described only once in the US in a recent UK emigrant

36. September 27, 2005HHS/FDA/CDRH36 Does vCJD Increase the Risk of Iatrogenic TSE transmission? Patients with variant CJD (vCJD) have greater extra- neural tissue burdens of PrP res Patients with variant CJD (vCJD) have greater extra- neural tissue burdens of PrP res Patients with vCJD may have atypical and prolonged symptoms before diagnosis Patients with vCJD may have atypical and prolonged symptoms before diagnosis The number of patients with presymptomatic vCJD may be increasing The number of patients with presymptomatic vCJD may be increasing There is concern that the risk of vCJD transmission by surgical instruments may be increasing in areas affected by the BSE epidemic and may involve other tissues besides CNS tissues There is concern that the risk of vCJD transmission by surgical instruments may be increasing in areas affected by the BSE epidemic and may involve other tissues besides CNS tissues

37. September 27, 2005HHS/FDA/CDRH37 Summary TSEs are rare, fatal neurodegenerative diseases of man and animals TSEs are rare, fatal neurodegenerative diseases of man and animals TSE has, very rarely, been transmitted by contaminated surgical instruments TSE has, very rarely, been transmitted by contaminated surgical instruments Current clinical practice based on the CDC recommendations may reduce the risk of TSE transmission by contaminated instruments Current clinical practice based on the CDC recommendations may reduce the risk of TSE transmission by contaminated instruments Is it possible to further reduce the risk? Is it possible to further reduce the risk?

38. September 27, 2005HHS/FDA/CDRH38

39. September 27, 2005HHS/FDA/CDRH39 In-Vivo Models of TSE Transmission Experimental Design Issues Sheila A. Murphey, MD Branch Chief Infection Control Devices Branch Division of Anesthesiology, General Hospital, Infection Control and Dental Devices Center for Devices and Radiologic Health

40. September 27, 2005HHS/FDA/CDRH40 Experimental Methods for Studying TSE Methods Can Examine Transmissibility Instrument Proxies In-Vivo Models YESYES ImmunoassaysNONO Cell Culture NONO

41. September 27, 2005HHS/FDA/CDRH41 In-Vivo Models of TSE Transmission Prion source Prion source Susceptible host animal Susceptible host animal CNS introduction CNS introduction Observe host for symptoms of TSE or sacrifice asymptomatic survivors at predetermined endpoint Observe host for symptoms of TSE or sacrifice asymptomatic survivors at predetermined endpoint Confirm outcome by examination of CNS for evidence of TSE infection Confirm outcome by examination of CNS for evidence of TSE infection

42. September 27, 2005HHS/FDA/CDRH42 In-Vivo Models of TSE Transmission Prion Sources Human CJD- sporadic Human CJD- sporadic - variant - genetic Scrapie Scrapie Bovine Spongiform Encephalopathy (BSE) Bovine Spongiform Encephalopathy (BSE) Other Animal Prions Other Animal Prions

43. September 27, 2005HHS/FDA/CDRH43 In-Vivo Models of TSE Transmission Most Common Hosts Most Common Hosts Mice Mice Hamsters Hamsters Guinea Pig Guinea Pig Hosts may be genetically altered to carry other species’ PrP c Hosts may be genetically altered to carry other species’ PrP c Host lifespan may differ from original host. Will this affect the natural history of infection or the interpretation of results? Host lifespan may differ from original host. Will this affect the natural history of infection or the interpretation of results?

44. September 27, 2005HHS/FDA/CDRH44 In-Vivo Models of TSE Transmission Overcoming Species Barriers to TSE Transmission Overcoming Species Barriers to TSE Transmission Large infecting inoculum Large infecting inoculum Serial passage in new host Serial passage in new host Genetic manipulation of the host by introducing a new PrP sen Genetic manipulation of the host by introducing a new PrP sen

45. September 27, 2005HHS/FDA/CDRH45 In-Vivo Models of TSE Transmission Introduction of TSE Sources into CNS Introduction of TSE Sources into CNS Whole brain tissue Whole brain tissue Homogenates of brain Homogenates of brain Material may be diluted Material may be diluted Material may be pooled from several sources Material may be pooled from several sources Material may have been frozen before use Material may have been frozen before use

46. September 27, 2005HHS/FDA/CDRH46 In-Vivo Models of TSE Transmission Introduction of Inoculum into CNS Introduction of Inoculum into CNS Injection by needle Injection by needle Coated stainless steel wire – may be left in-situ or removed after insertion Coated stainless steel wire – may be left in-situ or removed after insertion Coated stainless steel spheres Coated stainless steel spheres

47. September 27, 2005HHS/FDA/CDRH47 In-Vivo Models for TSE Transmission Experimental Model New steel needle New stainless steel wire New stainless steel spheres Real Instruments Aged, pitted surface Steel, various metal alloys, other materials Complex shapes Hard to clean areas Hinged surfaces Hinged surfaces Mated surfaces Mated surfaces Lumens Lumens

48. September 27, 2005HHS/FDA/CDRH48

49. September 27, 2005HHS/FDA/CDRH49

50. September 27, 2005HHS/FDA/CDRH50

51. September 27, 2005HHS/FDA/CDRH51 In-Vivo Models of TSE Transmission Serial laboratory passage of prions may alter strain characteristics Serial laboratory passage of prions may alter strain characteristics AG Dickinson, DM Taylor NEJM 1978 229:1413-1414 AG Dickinson, DM Taylor NEJM 1978 229:1413-1414 Scrapie strain inactivation at 126 0 C Scrapie strain inactivation at 126 0 C Strain 139A 2 hrs Strain 139A 2 hrs Strain 22A 4 hrs Strain 22A 4 hrs

52. September 27, 2005HHS/FDA/CDRH52 In-Vivo Models of TSE Transmission Sources of Variability in the Prion Source One infected brain as the source or several? One infected brain as the source or several? Inoculum prepared once or several times? Inoculum prepared once or several times? Inoculation of host animals on one day or over several days? Inoculation of host animals on one day or over several days? Has variation in the inoculum load on the wire been measured? Has variation in the inoculum load on the wire been measured?

53. September 27, 2005HHS/FDA/CDRH53 In-Vivo Models of TSE Transmission Sources of Variability in Host Maintenance Groups inoculated on same day? Groups inoculated on same day? Groups in 1 or more cages? Groups in 1 or more cages? Groups on same shelf? Same rack? Groups on same shelf? Same rack? Intercurrent deaths must be considered in the statistical analysis of the results Intercurrent deaths must be considered in the statistical analysis of the results

54. September 27, 2005HHS/FDA/CDRH54 In-Vivo Models of TSE Transmission Confirmation of the CNS Status of TSE-Exposed Hosts – Is Observation for Symptoms Enough? Is Observation for Symptoms Enough? Jackson G,McKintosh E, Flechsig E et al. J Gen Virol 2005 86:869-878 Jackson G,McKintosh E, Flechsig E et al. J Gen Virol 2005 86:869-878 “While autoclaving appeared to be effective, histologic examination of clinically unaffected animals revealed signs of infection in 2 of 6 animals from the 121 0 C group and 1 of 4 animals from the 134 0 C group”. “While autoclaving appeared to be effective, histologic examination of clinically unaffected animals revealed signs of infection in 2 of 6 animals from the 121 0 C group and 1 of 4 animals from the 134 0 C group”. This was also noted in 2 other experimental groups; 4 of 5 animals in the LpHse group and 1 of 5 in the Enzymes = autoclaved at 134 0 C group. This was also noted in 2 other experimental groups; 4 of 5 animals in the LpHse group and 1 of 5 in the Enzymes = autoclaved at 134 0 C group.

55. September 27, 2005HHS/FDA/CDRH55 In Vivo Models of TSE Transmission Experimental models examine whether or not TSE is transmitted Experimental models examine whether or not TSE is transmitted The presence or absence of TSE infection in all experimental animals must be determined The presence or absence of TSE infection in all experimental animals must be determined Asymptomatic, sacrificed animals may have TSE infection Asymptomatic, sacrificed animals may have TSE infection

56. September 27, 2005HHS/FDA/CDRH56 In-Vivo Models of TSE Transmission How closely does the experimental process reflect actual clinical practice? How closely does the experimental process reflect actual clinical practice? Surgical instruments are normally cleaned, packaged for sterilization and re-sterilized after each use. Will all of these steps be included in the study intended to validate the use of a product on surgical instruments? Surgical instruments are normally cleaned, packaged for sterilization and re-sterilized after each use. Will all of these steps be included in the study intended to validate the use of a product on surgical instruments?

57. September 27, 2005HHS/FDA/CDRH57 In-Vivo Models of TSE Transmission How closely does the experimental process reflect actual clinical practice? How closely does the experimental process reflect actual clinical practice? Will “cleaning” differ for 5mm wires versus an instrument? Will technique, cleaning agents, temperature, etc. vary? Will “cleaning” differ for 5mm wires versus an instrument? Will technique, cleaning agents, temperature, etc. vary? Will “cleaning” a 5mm wire remove so much inoculum that the experimental outcome would be affected? How could removal be measured? Will “cleaning” a 5mm wire remove so much inoculum that the experimental outcome would be affected? How could removal be measured?

58. September 27, 2005HHS/FDA/CDRH58 In-Vivo Models of TSE Transmission How closely does the experimental process reflect actual clinical practice? How closely does the experimental process reflect actual clinical practice? Will the 5mm wire be “packaged” for sterilization in the same way as an instrument? (Instruments may be placed in wrapped trays or in sterilization “pouches” before sterilization.) Will the 5mm wire be “packaged” for sterilization in the same way as an instrument? (Instruments may be placed in wrapped trays or in sterilization “pouches” before sterilization.)

59. September 27, 2005HHS/FDA/CDRH59 In-Vivo Models of TSE Transmission How closely does the experimental process reflect actual clinical practice? How closely does the experimental process reflect actual clinical practice? Will cleaning be performed with standard products in clinical use? Will cleaning be performed with standard products in clinical use? Will sterilizer cycles normally used in hospitals be included in the experimental design? Will sterilizer cycles normally used in hospitals be included in the experimental design?

60. September 27, 2005HHS/FDA/CDRH60 In-Vivo Models of TSE Transmission Calculated Endpoints for TSE Transmission Median Incubation Period Median Incubation Period Median Survival Median Survival Percent Survival Percent Survival Log Reduction in Infectivity Log Reduction in Infectivity

61. September 27, 2005HHS/FDA/CDRH61 In-Vivo Models of TSE Transmission Calculated endpoints for TSE Transmission The “control” curve is created by administering serial dilutions of the untreated inoculum and observing the outcomes The “control” curve is created by administering serial dilutions of the untreated inoculum and observing the outcomes The “experimental” group outcomes are compared to the “controls” The “experimental” group outcomes are compared to the “controls”

62. September 27, 2005HHS/FDA/CDRH62 In-Vivo Models of TSE Transmission As the TSE dose in the serial dilutions of the untreated inoculum decreases. As the TSE dose in the serial dilutions of the untreated inoculum decreases. Median incubation period to symptoms increases Median incubation period to symptoms increases Survival without infection begins to occur below the ID 100 dose Survival without infection begins to occur below the ID 100 dose At the ID 50 dose, half of the exposed animals will survive without infection At the ID 50 dose, half of the exposed animals will survive without infection

63. September 27, 2005HHS/FDA/CDRH63 In-Vivo Models of TSE Transmission “Log Reduction in Infectivity” as an Endpoint Magnitude of CNS infection varies (10 7 to 10 11 LD 50 /g brain) by model system (Prion/Host) Magnitude of CNS infection varies (10 7 to 10 11 LD 50 /g brain) by model system (Prion/Host) Magnitude of the possible reduction can vary by model system Magnitude of the possible reduction can vary by model system “Measurement” requires comparison to the “dilution curve” “Measurement” requires comparison to the “dilution curve”

64. September 27, 2005HHS/FDA/CDRH64 In-Vivo Models of TSE Transmission “Log Reduction in Infectivity” as an Endpoint Exact measurement of the CNS inoculum on a wire is difficult Exact measurement of the CNS inoculum on a wire is difficult “Reduction” is measured from the infecting dose on the wire to the estimated survival endpoint of the host “Reduction” is measured from the infecting dose on the wire to the estimated survival endpoint of the host Lower limit of detection for these models has not been determined Lower limit of detection for these models has not been determined

65. September 27, 2005HHS/FDA/CDRH65 In-Vivo Models of TSE Transmission Evaluation of Experimental Results Is there a measurable difference between the experimental and control groups? Is there a measurable difference between the experimental and control groups? What is the magnitude of the difference? What is the magnitude of the difference? How certain is the difference? How certain is the difference?

66. September 27, 2005HHS/FDA/CDRH66 In-Vivo Models of TSE Transmission Evaluation of Experimental Results Is the experimental difference Is the experimental difference Statistically Significant? Statistically Significant? Clinically Significant? Clinically Significant?

67. September 27, 2005HHS/FDA/CDRH67 In-Vivo Models of TSE Transmission Evaluation of Experimental Results Different model systems will produce different results. Different model systems will produce different results. Different prion characteristics such as sensitivity to heat inactivation. Different prion characteristics such as sensitivity to heat inactivation. Different magnitude of infection. Different magnitude of infection.

68. September 27, 2005HHS/FDA/CDRH68 In-Vivo Models of TSE Transmission Are in-vivo experimental model of TSE transmission results clinically relevant? Are in-vivo experimental model of TSE transmission results clinically relevant? Should current clinical practice be altered on the basis of such experimental results? Should current clinical practice be altered on the basis of such experimental results?

69. September 27, 2005HHS/FDA/CDRH69 Products/Processes which Reduce TSE Transmission Risk / Benefit Ratio

70. September 27, 2005HHS/FDA/CDRH70 Products/Processes which Reduce TSE Transmission Benefit Reduce the risk of transmission of Creutzfeldt-Jakob disease and other TSEs by contaminated surgical instruments Reduce the risk of transmission of Creutzfeldt-Jakob disease and other TSEs by contaminated surgical instruments

71. September 27, 2005HHS/FDA/CDRH71 Products/Processes which Reduce TSE Transmission Risks False sense of security about the risk of transmitting TSE by contaminated instruments False sense of security about the risk of transmitting TSE by contaminated instruments Failure to adequately follow practices currently recommended to reduce the risk of TSE transmission by contaminated instruments Failure to adequately follow practices currently recommended to reduce the risk of TSE transmission by contaminated instruments

72. September 27, 2005HHS/FDA/CDRH72 Products/Processes which Reduce TSE Transmission Risks Less attention to identifying patients with possible CJD before invasive procedures, especially neurosurgery Less attention to identifying patients with possible CJD before invasive procedures, especially neurosurgery Less attention to quarantining, discarding or specially processing instruments used in invasive procedures on patients with possible or definite CJD Less attention to quarantining, discarding or specially processing instruments used in invasive procedures on patients with possible or definite CJD

73. September 27, 2005HHS/FDA/CDRH73 Products/Processes which Reduce TSE Transmission Risks Less attention to carefully cleaning contaminated surgical instruments Less attention to carefully cleaning contaminated surgical instruments Less willingness to follow current CDC recommendations for handling instruments possibly contaminated by CJD Less willingness to follow current CDC recommendations for handling instruments possibly contaminated by CJD Less willingness to discard hard-to-clean contaminated instruments possibly contaminated by CJD Less willingness to discard hard-to-clean contaminated instruments possibly contaminated by CJD

74. September 27, 2005HHS/FDA/CDRH74 Products/Processes which Reduce TSE Transmission Is the clinical benefit of approving potential products/processes which reduce TSE transmission from its current level significant? Is the clinical benefit of approving potential products/processes which reduce TSE transmission from its current level significant? Does this benefit outweigh the possible risks? Does this benefit outweigh the possible risks?

75. September 27, 2005HHS/FDA/CDRH75

76. Statistical Considerations: Design and Analysis Estelle Russek-Cohen, Ph.D. Team Leader Division of Biostatistics Center for Devices and Radiological Health Food and Drug Administration

77. September 27, 2005HHS/FDA/CDRH77 Outline Background Background Key components to Study Designs Key components to Study Designs Log reduction endpoint Log reduction endpoint Improving survival or time to first symptoms Improving survival or time to first symptoms Data analysis Issues Data analysis Issues Conclusions Conclusions

78. September 27, 2005HHS/FDA/CDRH78 Valid Scientific Evidence Studies presented must support intended use claim Studies presented must support intended use claim Study requirements: Study requirements: Product must be tested to support labeling instructions Product must be tested to support labeling instructions Conclusions must have a degree of confidence (e.g. statistical significance) Conclusions must have a degree of confidence (e.g. statistical significance)

79. September 27, 2005HHS/FDA/CDRH79 Previously Published Papers 1-3 cages of animals per treatment 1-3 cages of animals per treatment 4-12 animals per treatment 4-12 animals per treatment Single source of TSE-infected brain material Single source of TSE-infected brain material 1 to 5 brains used 1 to 5 brains used Infected homogenate or infected wire Infected homogenate or infected wire 1-2 batches of “cleaner” 1-2 batches of “cleaner” All in controlled research environment All in controlled research environment

80. September 27, 2005HHS/FDA/CDRH80 Key Components to Study Design Lengthy incubation period: Lengthy incubation period: 1-2 year study is needed 1-2 year study is needed On each animal can record: On each animal can record: Survives (Y/N) beyond fixed time period Survives (Y/N) beyond fixed time period  Percent survival  Percent survival less efficient statistically less efficient statistically Time until death or (??) symptoms * Time until death or (??) symptoms *  Median survival  Median survival * Can consider competing causes of death

81. September 27, 2005HHS/FDA/CDRH81 Competing Causes of Death Ignoring competing causes of death introduces bias. Ignoring competing causes of death introduces bias. If animal dies, we expect it will be necropsied. If animal dies, we expect it will be necropsied. If animal has prion disease at time of death but death is not due to prion disease, we can consider it as a death due to to prion disease. If animal has prion disease at time of death but death is not due to prion disease, we can consider it as a death due to to prion disease.

82. September 27, 2005HHS/FDA/CDRH82 Limitations How much material sticks to the wire? How much material sticks to the wire? Does it vary within treatment? Does it vary within treatment? Does it depend on geometry? Does it depend on geometry? Does it depend on matrix? Does it depend on matrix? Does homogenizing impact results? Does homogenizing impact results? How does it depend on animal model and type of TSE? How does it depend on animal model and type of TSE? Relevance to humans? Relevance to humans?

83. September 27, 2005HHS/FDA/CDRH83 “Extraneous” Variables Technician Technician Animal to animal variation Animal to animal variation Housing 4-5 animals/cage Housing 4-5 animals/cage Cages are in batteries Cages are in batteries Variation in strength of initial inoculate Variation in strength of initial inoculate Lot-to-lot variation in product Lot-to-lot variation in product

84. September 27, 2005HHS/FDA/CDRH84 A Cage Battery

85. September 27, 2005HHS/FDA/CDRH85 Properties of good experimental design Absence of systematic error Absence of systematic error Precision of endpoint Precision of endpoint Range of validity Range of validity Simplicity Simplicity Calculation of uncertainty Calculation of uncertainty D.R. Cox: Planning of Experiments D.R. Cox: Planning of Experiments

86. September 27, 2005HHS/FDA/CDRH86 Properties of good experimental design Absence of systematic error Absence of systematic error Reduce bias Reduce bias Precision of endpoint Precision of endpoint Time to death rather than yes or no Time to death rather than yes or no Range of validity Range of validity Do “extraneous variables” impact performance? Do “extraneous variables” impact performance? Simplicity Simplicity Calculation of uncertainty Calculation of uncertainty Reporting confidence intervals or levels of significance Reporting confidence intervals or levels of significance D.R. Cox: Planning of Experiments D.R. Cox: Planning of Experiments

87. September 27, 2005HHS/FDA/CDRH87 Components of Good Study Design Reduce bias via randomization: Reduce bias via randomization: Randomization of animals to cages and then randomize cages to treatments Randomization of animals to cages and then randomize cages to treatments Randomization of order in which treatment is administered Randomization of order in which treatment is administered Concurrent application of all experimental and control group(s) Concurrent application of all experimental and control group(s)

88. September 27, 2005HHS/FDA/CDRH88 Experimental Unit Each cage is randomized to a single treatment, thus each cage is an experimental unit. Each cage is randomized to a single treatment, thus each cage is an experimental unit. Observations within cage are not independent Observations within cage are not independent This is not just because: This is not just because: Disease is infectious Disease is infectious Analysis must reflect this: Analysis must reflect this: Standard for Veterinary submissions at FDA Standard for Veterinary submissions at FDA

89. September 27, 2005HHS/FDA/CDRH89 Quantifying Benefit Most common in prion literature: Most common in prion literature: Log reduction endpoint Log reduction endpoint Example: 6 log reduction endpoint Example: 6 log reduction endpoint For every 1 million infectious particles (10 6 )…..1 particle remains For every 1 million infectious particles (10 6 )…..1 particle remains Before After Before After 10 8 /gm 10 2 /gm 10 8 /gm 10 2 /gm Used in virology and bacteriology Used in virology and bacteriology

90. September 27, 2005HHS/FDA/CDRH90 Controls: Log Reduction Endpoint (no cleaning or disinfection) Controls: to establish a standard curve Controls: to establish a standard curve Controls: animals exposed to varying levels of infected material Controls: animals exposed to varying levels of infected material TSE infected inoculate is diluted in a series of 10-fold dilutions (.1,.01,.001,…) TSE infected inoculate is diluted in a series of 10-fold dilutions (.1,.01,.001,…) How is dilution prepared and how does it impact sticking to wire? How is dilution prepared and how does it impact sticking to wire?

91. September 27, 2005HHS/FDA/CDRH91 Treatment Using Product Use undiluted homogenate to infect wire Use undiluted homogenate to infect wire Apply product to disinfect as on label Apply product to disinfect as on label As in controls, use wires to infect clean animals As in controls, use wires to infect clean animals Calculate outcomes as in controls Calculate outcomes as in controls See which dilution level it compares to See which dilution level it compares to

92. September 27, 2005HHS/FDA/CDRH92 Hypothetical Data Let dilution level = Let dilution level = -log10(proportion infected material) -log10(proportion infected material) e.g. Dilution level=1: e.g. Dilution level=1: 10% =>.10 => 10 -1 10% =>.10 => 10 -1 Assume enough animals for each dilution level to reasonably estimate percent survival Assume enough animals for each dilution level to reasonably estimate percent survival

93. September 27, 2005HHS/FDA/CDRH93 Estimating Log Reduction Hypothetical example 123456789 Dilution Level 0.0 0.2 0.4 0.6 0.8 1.0 Survival Rate Test Group

94. September 27, 2005HHS/FDA/CDRH94 Limitations of Log Reduction Study Complex design issues with log reduction endpoint Complex design issues with log reduction endpoint Large numbers of controls Large numbers of controls Each dilution level =group of animals Each dilution level =group of animals i.e. 9 dilutions= 9 groups Hard to balance 9+1=10 groups over: Hard to balance 9+1=10 groups over: timing, housing, batches of product timing, housing, batches of product Sponsor resources: lots of control animals Sponsor resources: lots of control animals Indirect endpoint: one assumes log reduction does not depend on size of initial inoculate Indirect endpoint: one assumes log reduction does not depend on size of initial inoculate

95. September 27, 2005HHS/FDA/CDRH95 Single “Disinfectant” Group Single Control Group No log reduction endpoint No log reduction endpoint Uses standard operating procedure with untreated homogenate+wire Uses standard operating procedure with untreated homogenate+wire Still measure either: Still measure either: Survival (Y/N) Survival (Y/N) Time until death or onset of symptoms Time until death or onset of symptoms Simpler design: easier to control extraneous factors Simpler design: easier to control extraneous factors Analysis and sample size needs are simpler to determine Analysis and sample size needs are simpler to determine

96. September 27, 2005HHS/FDA/CDRH96 Repeat Experiment Over Time Not all animals have to be done at once Not all animals have to be done at once Can do fraction of study at each time: Can do fraction of study at each time: All treatments appear at each time All treatments appear at each time New lot of product at each time New lot of product at each time New batch of inoculate at each time New batch of inoculate at each time New cage batteries at each time New cage batteries at each time Animals can be of comparable ages Animals can be of comparable ages

97. September 27, 2005HHS/FDA/CDRH97 Advantages: Replicating Over Time Assesses overall reproducibility of study Assesses overall reproducibility of study With both log reduction study and two group study: there will be variation in initial inoculate With both log reduction study and two group study: there will be variation in initial inoculate Reproducibility in time is a compromise because reproducibility over sites is not feasible. Reproducibility in time is a compromise because reproducibility over sites is not feasible.

98. September 27, 2005HHS/FDA/CDRH98 Data Analysis Many journal articles do NOT present formal statistical analyses Many journal articles do NOT present formal statistical analyses (e.g. no 95% confidence intervals) (e.g. no 95% confidence intervals) Valid scientific evidence requires an appropriate statistical analysis Valid scientific evidence requires an appropriate statistical analysis Analysis should be consistent with study design Analysis should be consistent with study design

99. September 27, 2005HHS/FDA/CDRH99 Sample Sizes: Simple Design Consider case of two groups: Consider case of two groups: One control and one disinfectant One control and one disinfectant Consider a binary endpoint: Consider a binary endpoint: Animal dies or does not die of disease Animal dies or does not die of disease Enough control animals to establish inoculate is sufficiently deadly Enough control animals to establish inoculate is sufficiently deadly Enough treatment animals to say at least 99% will survive disease Enough treatment animals to say at least 99% will survive disease

100. September 27, 2005HHS/FDA/CDRH100 The Numbers 2 cages of animals at each time point to establish inoculate is sufficiently infectious 2 cages of animals at each time point to establish inoculate is sufficiently infectious EXPECT 100% MORTALITY EXPECT 100% MORTALITY In treatment group: In treatment group: EXPECT 100% SURVIVAL EXPECT 100% SURVIVAL Lower 95% confidence bound >99% Lower 95% confidence bound >99% Need 1-3/N>.99 or 300 Animals Need 1-3/N>.99 or 300 Animals This ignores cage effect. This ignores cage effect.

101. September 27, 2005HHS/FDA/CDRH101 Precision of survival estimates 75 cages with 4 animals With 90% survival and no cage effects: With 90% survival and no cage effects: 95%CI (88.3%, 94.8%) 95%CI (88.3%, 94.8%) If within cage effects are very strong, e.g. all animals die w/in cage or none die If within cage effects are very strong, e.g. all animals die w/in cage or none die Confidence bound is determined by: number of cages…not number animals Confidence bound is determined by: number of cages…not number animals 95% CI: (83.4%, 97.0%) 95% CI: (83.4%, 97.0%)

102. September 27, 2005HHS/FDA/CDRH102 95% Lower Confidence Bound: Observe 100% survival Depends on number of animals: NumberIndependence Complete Dependence 1277.9%36.8% 3692.0%71.7% 9696.9%88.3% 20098.5%94.2% 30099.0%96.1%

103. September 27, 2005HHS/FDA/CDRH103 Time to event data: Survival or time to onset of symptoms Sample size will vary by: Sample size will vary by: Animal model; source of prion and survival/symptoms. Animal model; source of prion and survival/symptoms. Need preliminary data: Need preliminary data: Median survival due to competing causes Median survival due to competing causes Median survival in control group or groups in case of log reduction endpoint Median survival in control group or groups in case of log reduction endpoint Median survival in group treated with product would be needed Median survival in group treated with product would be needed

104. September 27, 2005HHS/FDA/CDRH104 Same considerations Lot-to-lot variation in product Lot-to-lot variation in product Amount of infectious material in inoculate Amount of infectious material in inoculate Cage effects still matter Cage effects still matter If competing causes are frequent, need bigger N If competing causes are frequent, need bigger N Statistical efficiency is driven by number of deaths due to prion disease. Statistical efficiency is driven by number of deaths due to prion disease.

105. September 27, 2005HHS/FDA/CDRH105 Conclusions Details of a specific design will vary with experimental model Details of a specific design will vary with experimental model Key sources of variation need to be considered in design and analysis Key sources of variation need to be considered in design and analysis Design should consider experimental units Design should consider experimental units Study must be sized sufficiently to establish product effectiveness with an appropriate level of certainty Study must be sized sufficiently to establish product effectiveness with an appropriate level of certainty

106. September 27, 2005HHS/FDA/CDRH106

107. Iatrogenic CJD Risk from Reprocessed Neurosurgical Instruments Ron Brown Leader Laboratory of Biological Risk Assessment Office of Science and Engineering Laboratories Center for Devices and Radiological Health

108. September 27, 2005HHS/FDA/CDRH108 Goals Assess the annual risk of iatrogenic CJD in the US in patients undergoing neurosurgery with reprocessed neurosurgical instruments. Assess the annual risk of iatrogenic CJD in the US in patients undergoing neurosurgery with reprocessed neurosurgical instruments. Does not address risk of iatrogenic CJD from instruments used at extraneural sites. Does not address risk of iatrogenic CJD from instruments used at extraneural sites.

109. September 27, 2005HHS/FDA/CDRH109 Overview Provide overview of modeling approaches to estimate risk Provide overview of modeling approaches to estimate risk Provide justification for parameter values used in the models Provide justification for parameter values used in the models Underscore uncertainty associated with parameter values Underscore uncertainty associated with parameter values Assess impact of parameter values on estimated risk Assess impact of parameter values on estimated risk

110. September 27, 2005HHS/FDA/CDRH110 Risk of TSE transmission Likely frequency of a “transmissible” encounter (probability of exposure) Likely frequency of a “transmissible” encounter (probability of exposure) Availability of a TSE source (amount of TSE agent to which the patient is exposed) Availability of a TSE source (amount of TSE agent to which the patient is exposed) Effective TSE dose (infectivity) Effective TSE dose (infectivity)

111. September 27, 2005HHS/FDA/CDRH111 Risk Assessment Paradigm NAS/NRC (1983) Hazard Identification Hazard Identification Can CJD-infected CNS tissue serve as a source of iatrogenic transmission of CJD? Can CJD-infected CNS tissue serve as a source of iatrogenic transmission of CJD? Exposure Assessment Exposure Assessment What is the dose of infected material transferred to the patient? Dose-Response Assessment Dose-Response Assessment What is the relationship between the dose of TSE-contaminated material and the incidence of infection? Risk Characterization Risk Characterization What is the risk posed by exposure to TSE-contaminated material?

112. September 27, 2005HHS/FDA/CDRH112 Hazard Identification Widely understood that the abnormal form of prion protein is the etiologic agent for CJD in humans. Widely understood that the abnormal form of prion protein is the etiologic agent for CJD in humans. Iatrogenic transmission of CJD is rare, but has been reported following the use of contaminated depth EEG electrodes (Bernoulli et al., 1977), dura mater grafts (CDC, 2003) and neurosurgical instruments (Brown et al. 2000). Iatrogenic transmission of CJD is rare, but has been reported following the use of contaminated depth EEG electrodes (Bernoulli et al., 1977), dura mater grafts (CDC, 2003) and neurosurgical instruments (Brown et al. 2000).

113. September 27, 2005HHS/FDA/CDRH113 Exposure Assessment Probability of exposure Number of neurosurgeries performed annually in US (N) Number of neurosurgeries performed annually in US (N) Proportion of the population that is infected with CJD (P) Proportion of the population that is infected with CJD (P)

114. September 27, 2005HHS/FDA/CDRH114 Exposure Assessment Dose to patient Total mass of tissue remaining on surgical instruments after use (M) Total mass of tissue remaining on surgical instruments after use (M) Transfer of material from instruments to patients (T) Transfer of material from instruments to patients (T) Efficacy of routine cleaning methods (C) Efficacy of routine cleaning methods (C) Efficacy of routine sterilization methods (S) Efficacy of routine sterilization methods (S)

115. September 27, 2005HHS/FDA/CDRH115 Dose-Response Assessment Infectivity of the tissue transferred to the patient (I), represented as an intercerebral ID50. Assumptions Linear dose-response assessment Linear dose-response assessment All exposed individuals are vulnerable to infection, genetic variations only affect incubation period. All exposed individuals are vulnerable to infection, genetic variations only affect incubation period. Similar dose-response relationship in experimental animals and humans Similar dose-response relationship in experimental animals and humans

116. September 27, 2005HHS/FDA/CDRH116 Annual Infection Risk [N x P] x [M x T] x 0.5 I [C x S] Number of neurosurgeries performed annually in US (N) Number of neurosurgeries performed annually in US (N) Proportion of the population that is infected with sCJD (P) Proportion of the population that is infected with sCJD (P) Total mass of tissue remaining on surgical instruments (M) Total mass of tissue remaining on surgical instruments (M) Transfer of material from instruments to patients (T) Transfer of material from instruments to patients (T) Infectivity of tissue (I) Infectivity of tissue (I) Efficacy of routine cleaning methods (C) Efficacy of routine cleaning methods (C) Efficacy of routine sterilization methods (S) Efficacy of routine sterilization methods (S)

117. September 27, 2005HHS/FDA/CDRH117 Models Used Deterministic Uses point estimates for input parameters Uses point estimates for input parameters See only one solution at a time See only one solution at a time Ask “what if” questions Ask “what if” questions Annual infection risk equation in Excel Annual infection risk equation in Excel Default parameter values Default parameter values

118. September 27, 2005HHS/FDA/CDRH118 Models Used Probabilistic Monte Carlo method Monte Carlo method Repeatedly samples values from the probability distributions for the variables Repeatedly samples values from the probability distributions for the variables Allows examination of aggregate uncertainties and to derive risk ranges. Allows examination of aggregate uncertainties and to derive risk ranges. RiskAmp Monte Carlo add-in for Excel RiskAmp Monte Carlo add-in for Excel

119. September 27, 2005HHS/FDA/CDRH119 Number of Neurosurgical Procedures (N) CDC data (1996) CDC data (1996) 104,000 surgeries involving skull, brain 104,000 surgeries involving skull, brain and cerebral meninges and cerebral meninges Barker and Anim-Hanjani (2004) Barker and Anim-Hanjani (2004) Craniotomy data; 70,800 – 1988; 105,300 – 2001 4% increase/year Default value: 125,000 neurosurgeries in 2005

120. September 27, 2005HHS/FDA/CDRH120 Proportion of Neurosurgeries Conducted on Patients with sCJD (P) Annual incidence of sCJD (not vCJD) in US population: 1 in 1 million (1 x 10 -6 ) Annual incidence of sCJD (not vCJD) in US population: 1 in 1 million (1 x 10 -6 ) Prevalence of subclinical disease is unknown. Assume background rate of asymptomatic CJD is higher Prevalence of subclinical disease is unknown. Assume background rate of asymptomatic CJD is higher Default value: 2 x 10 -6 Default value: 2 x 10 -6 Range 1-10 x 10 -6 Range 1-10 x 10 -6

121. September 27, 2005HHS/FDA/CDRH121 Tissue Mass on Instruments (M) Assumptions from UK DOH (2001) risk assessment of vCJD. Expert judgement from panel. Assumptions from UK DOH (2001) risk assessment of vCJD. Expert judgement from panel. 10 mg of tissue on instruments after use 10 mg of tissue on instruments after use 20 instruments/procedure 20 instruments/procedure Default Value: Default Value: 1 x 10-2 g tissue/instrument x 20 instruments = 0.2 g tissue; Range 0.1 – 0.5 g tissue Range 0.1 – 0.5 g tissue

122. September 27, 2005HHS/FDA/CDRH122 Transfer of Tissue to Patients (T) Range used in UK DOH (2001) risk assessment: 0.0001 - 1 Range used in UK DOH (2001) risk assessment: 0.0001 - 1 Default assumption used in UK DOH (2001) risk assessment: 10% of material transferred upon reuse. Default assumption used in UK DOH (2001) risk assessment: 10% of material transferred upon reuse.

123. September 27, 2005HHS/FDA/CDRH123 Routine Cleaning Efficiency Alfa et al. (1999) Device Log 10 reduction in protein contamination Log 10 reduction in microbial contamination Bronchoscope0.661.85 Duodenoscope0.992.05 Colonoscope1.624.19

124. September 27, 2005HHS/FDA/CDRH124 Routine Cleaning Efficiency Verjat et al. (1999) Washing with detergents reduces proteins on flat surfaces by 5 logs Verjat et al. (1999) Washing with detergents reduces proteins on flat surfaces by 5 logs Smith et al. (in press) Residual protein on dental instruments – mean 5.4 ug. Smith et al. (in press) Residual protein on dental instruments – mean 5.4 ug. 3 log reduction if we start with 10 mg. 3 log reduction if we start with 10 mg. Default 2 log reduction, range 1-5 log Default 2 log reduction, range 1-5 log

125. September 27, 2005HHS/FDA/CDRH125 Routine Sterilization Efficacy Assumption used in UK DOH (2001) risk assessment: Sterilization reduces infectivity of prion protein by 3-6 logs. Assumption used in UK DOH (2001) risk assessment: Sterilization reduces infectivity of prion protein by 3-6 logs. Similar range of values used in this risk assessment. Default = 4 log reduction Similar range of values used in this risk assessment. Default = 4 log reduction

126. September 27, 2005HHS/FDA/CDRH126 Cleaning and Sterilization Efficiency Default assumptions Cleaning: 2 log 10 reductions in infectivity Cleaning: 2 log 10 reductions in infectivity Sterilization: 4 log 10 reductions in infectivity Sterilization: 4 log 10 reductions in infectivity Product of C x S = 1 x 10 6 Product of C x S = 1 x 10 6

127. September 27, 2005HHS/FDA/CDRH127 Tissue Infectivity (I) UK DOH (2001) risk assessment assumed value of 10 8 ic ID50/g brain tissue for subclinical disease. UK DOH (2001) risk assessment assumed value of 10 8 ic ID50/g brain tissue for subclinical disease. Based on unpublished studies of tissues from deceased vCJD patients (Bruce, 2000 cited in UK DOH, 2001) and the data on experimental scrapie in mice reported by Kimerberlin and Walker (1979). Based on unpublished studies of tissues from deceased vCJD patients (Bruce, 2000 cited in UK DOH, 2001) and the data on experimental scrapie in mice reported by Kimerberlin and Walker (1979). No stratification for age No stratification for age

128. September 27, 2005HHS/FDA/CDRH128 Annual Infection Risk [N x P] x [M x T] x 0.5 I [C x S] 0.25 infections/year Parameter Default Value N 1.25 x 10 5 P 2 x 10 -6 M 2 x 10 -1 T 1 x 10 -1 I 1 x 10 8 C 1 x 10 2 S 1 x 10 4

129. September 27, 2005HHS/FDA/CDRH129 Deterministic Model Evaluation of various scenarios Effectiveness of Routine Cleaning/Sterilization Log reduction in infectivity Infectivity of tissue (ID50) 10 7 10 8 10 9 42.525250 50.252.525 60.0250.252.5 70.00250.0250.25 80.000250.00250.025 90.0000250.000250.0025

130. September 27, 2005HHS/FDA/CDRH130 Probabilistic Model Distribution types

131. September 27, 2005HHS/FDA/CDRH131 Parameter Lower-bound estimate Default estimate Upper-bound estimate Number of neurosurgeries/ year in US (N) 1 x 10 5 1.25 x 10 5 1.5 x 10 5 Incidence of infection in the population (P) 1 x 10 -6 2 x 10 -6 1 x 10 -5 Mass of residual tissue (M) 0.10.20.5 Transfer of tissue to patient (T) 0.00010.11.0 Infectivity (I) 1 x 10 7 1 x 10 8 1 x 10 9 Cleaning efficiency 1 x 10 1 1 x 10 2 1 x 10 5 Sterilization efficiency (S) 1 x 10 3 1 x 10 4 1 x 10 6 Parameter Value Ranges

132. September 27, 2005HHS/FDA/CDRH132 Probabilistic Model Estimates of Annual Infection Rate (10,000 iterations) Upper-bound estimate of the background rate of asymptomatic CJD = 1 x 10 -5 Estimated infections/year in US Mean0.01 Percentile distribution 50.000049 250.000265 500.000868 750.003155 950.027090 1003.564

133. September 27, 2005HHS/FDA/CDRH133 Risk Characterization/Conclusions Based on the assumptions used in the risk assessment, the estimated annual iatrogenic CJD infection risk in US from use of reprocessed neurosurgical instruments: < 1 infection/year. Based on the assumptions used in the risk assessment, the estimated annual iatrogenic CJD infection risk in US from use of reprocessed neurosurgical instruments: < 1 infection/year. Estimates were derived using deterministic and probabilistic approaches. Both approaches allow examination of risk under differing model assumptions. Estimates were derived using deterministic and probabilistic approaches. Both approaches allow examination of risk under differing model assumptions. Uncertainty associated with parameter estimates and final risk estimates. Uncertainty associated with parameter estimates and final risk estimates. Risk estimates may be used to determine magnitude of the risk and the effectiveness of risk reduction measures. Risk estimates may be used to determine magnitude of the risk and the effectiveness of risk reduction measures.

134. September 27, 2005HHS/FDA/CDRH134

135. September 27, 2005HHS/FDA/CDRH135 _______________ PANEL QUESTIONS _______________

136. September 27, 2005HHS/FDA/CDRH136 Questions for the Advisory Panel 1.Assuming that a product sponsor seeks a claim for “Reducing TSE Infectivity” on stainless steel instruments, is it reasonable for such an indication to be validated using animal studies of TSE transmission? Please discuss.

137. September 27, 2005HHS/FDA/CDRH137 Questions for the Advisory Panel 2.Discuss the relevance of various design features of such validation studies.

138. September 27, 2005HHS/FDA/CDRH138 Questions for the Advisory Panel 3.Of the 3 study endpoints cited in the literature – log reduction in infectivity, mean incubation time and survival (median survival and percent survival), which, if any, may be adequate for the validation of a “Reducing TSE Infectivity” indication? Should demonstration of a particular level of reduction of TSE infectivity in one or more endpoints be expected in order to support a indication for use? Should demonstration of a particular level of reduction of TSE infectivity in one or more endpoints be expected in order to support a indication for use? How may clinical benefit be estimated from these endpoints? How may clinical benefit be estimated from these endpoints?

139. September 27, 2005HHS/FDA/CDRH139 Questions for the Advisory Panel 4.What additional issues should be considered by FDA when evaluating indications for use for devices other than simple surgical steel instruments? How can devices constructed from or including materials other than stainless steel, devices with complex shapes, devices with hinged or mated surfaces or devices with lumens be addressed?

140. September 27, 2005HHS/FDA/CDRH140 Questions for the Advisory Panel 5.How closely should the experimental treatment conditions for a product/process indicating to reduce TSE infectivity replicate the actual conditions under which the proposed product/process would actually be used? Should such issues as instrument cleaning, conditions which might fix protein to instruments, possible interactions between the new product/process and standard cleaning agents, sterilizer cycles used, etc., be considered?

141. September 27, 2005HHS/FDA/CDRH141 Questions for the Advisory Panel 6.Considering the current state of the science and existing investigative methods for estimating the potential for TSE transmission, can an indication for use of “complete elimination of TSE infectivity” be validated?