1. October 31, 2005HHS/FDA/CDRH1

2. October 31, 2005HHS/FDA/CDRH2 Scientific Issues in Evaluating Products Intended to Decontaminate Surgical instruments Exposed to TSE Agents Discussions of a Recent FDA Device Advisory Panel 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

3. 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

4. October 31, 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. October 31, 2005HHS/FDA/CDRH5 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

6. October 31, 2005HHS/FDA/CDRH6 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

7. October 31, 2005HHS/FDA/CDRH7 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.

8. October 31, 2005HHS/FDA/CDRH8 General Hospital and Personal Use Devices Panel Presentations by FDA Sheila A. Murphey, MD Elaine S. Mayhall, PhD Estelle Russek-Cohen, PhD Ronald Brown

9. October 31, 2005HHS/FDA/CDRH9 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

10. October 31, 2005HHS/FDA/CDRH10 Iatrogenic Transmission of Creutzfeldt-Jakob disease Source #Incubation period Neurosurgery 417 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

11. October 31, 2005HHS/FDA/CDRH11 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

12. October 31, 2005HHS/FDA/CDRH12 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.

13. October 31, 2005HHS/FDA/CDRH13 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?

14. October 31, 2005HHS/FDA/CDRH14 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

15. October 31, 2005HHS/FDA/CDRH15 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

16. October 31, 2005HHS/FDA/CDRH16

17. October 31, 2005HHS/FDA/CDRH17 Products/Processes which Reduce TSE Transmission Risk / Benefit Ratio

18. October 31, 2005HHS/FDA/CDRH18 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

19. October 31, 2005HHS/FDA/CDRH19 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

20. October 31, 2005HHS/FDA/CDRH20 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?

21. 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

22. October 31, 2005HHS/FDA/CDRH22 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)

23. October 31, 2005HHS/FDA/CDRH23 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

24. October 31, 2005HHS/FDA/CDRH24 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

25. October 31, 2005HHS/FDA/CDRH25 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

26. 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

27. October 31, 2005HHS/FDA/CDRH27 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.

28. October 31, 2005HHS/FDA/CDRH28 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

29. October 31, 2005HHS/FDA/CDRH29 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

30. October 31, 2005HHS/FDA/CDRH30 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

31. October 31, 2005HHS/FDA/CDRH31 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.

32. October 31, 2005HHS/FDA/CDRH32 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

33. October 31, 2005HHS/FDA/CDRH33 MHRA Comments New deactivation agents are being presented to the market where the models chosen may not be substantive enough to ensure the product/process is fully validated. New deactivation agents are being presented to the market where the models chosen may not be substantive enough to ensure the product/process is fully validated.

34. October 31, 2005HHS/FDA/CDRH34 MHRA Summary Understanding of prions and their adherence onto surgical instruments is advancing at a rapid pace, but what about other materials used in the manufacture of surgical instruments (eg titanium, plastics) Understanding of prions and their adherence onto surgical instruments is advancing at a rapid pace, but what about other materials used in the manufacture of surgical instruments (eg titanium, plastics) There does not appear to be agreement within the scientific community on the most appropriate animal/prion strain model that is representative of the human form of vCJD for use in research and product/process development There does not appear to be agreement within the scientific community on the most appropriate animal/prion strain model that is representative of the human form of vCJD for use in research and product/process development

35. October 31, 2005HHS/FDA/CDRH35 _______________ PANEL QUESTIONS _______________

36. October 31, 2005HHS/FDA/CDRH36 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.

37. October 31, 2005HHS/FDA/CDRH37 Answers from the Advisory Panel 1. The Advisory Panel agreed that yes, it is reasonable that a product claim for “Reducing TSE Infectivity” on stainless steel instruments be validated using animal studies of TSE transmission.

38. October 31, 2005HHS/FDA/CDRH38 Questions for the Advisory Panel 2.Discuss the relevance of various design features of such validation studies.

39. October 31, 2005HHS/FDA/CDRH39 Answers from the Advisory Panel 2. The Advisory Panel agreed that the following were relevant to validation studies for a claim of TSE reduction: Maximal study duration Maximal study duration Study population large enough for “sufficient statistical validity” Study population large enough for “sufficient statistical validity” Log reduction in infectivity should be as large as possible Log reduction in infectivity should be as large as possible

40. October 31, 2005HHS/FDA/CDRH40 Answers from the Advisory Panel 2. Relevant validation study features-cont. Human prion sources should be studied – both sporadic and variant CJD Human prion sources should be studied – both sporadic and variant CJD Transgenic mouse models are appropriate Transgenic mouse models are appropriate New clinical human CJD sources may be characterized against known animal TSE models and/or the WHO reference strains New clinical human CJD sources may be characterized against known animal TSE models and/or the WHO reference strains

41. October 31, 2005HHS/FDA/CDRH41 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?

42. October 31, 2005HHS/FDA/CDRH42 Answers from the Advisory panel 3. The Advisory panel agreed that “log reduction in infectivity” is the appropriate study endpoint for validation of “reducing TSE infectivity” claims. The Advisory Panel did not specify a particular level of reduction The Advisory Panel did not specify a particular level of reduction The Advisory Panel stated that linking the mean incubation time to log reduction in infectivity could demonstrate clinical relevance The Advisory Panel stated that linking the mean incubation time to log reduction in infectivity could demonstrate clinical relevance

43. October 31, 2005HHS/FDA/CDRH43 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?

44. October 31, 2005HHS/FDA/CDRH44 Answers from the Advisory Panel 4. Additional study issues which FDA should consider for claims for devices other than “simple” steel instruments modification of the test wire surface to better mimic clinical conditions modification of the test wire surface to better mimic clinical conditions testing different materials testing different materials testing simulated/surrogate device shapes testing simulated/surrogate device shapes

45. October 31, 2005HHS/FDA/CDRH45 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?

46. October 31, 2005HHS/FDA/CDRH46 Answers from the Advisory Panel 5. The panel agreed that yes, they wished to see the study conditions simulate the clinical conditions of instrument processing as closely as possible. The Panel specifically mentioned attention to the challenge of a large bioburden, dried on an instrument before processing.

47. October 31, 2005HHS/FDA/CDRH47 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?

48. October 31, 2005HHS/FDA/CDRH48 Answers from the Advisory Panel 6. The Advisory panel agreed that,given the current state of the science and the existing investigative methods available for estimating the potential for TSE transmission, a claim for “complete elimination of TSE infectivity” from surgical instruments cannot be validated at this time.