Scientific Issues in Evaluating Products Intended to Decontaminate Surgical instruments Exposed to TSE Agents

1. HHS/FDA/CDRH

2. 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 ChiefInfection Control Devices Branch Division of Anesthesiology, General Hospital, Infection Control and Dental Devices Center for Devices and Radiological Health HHS/FDA/CDRH

3. MEDICAL DEVICES ADVISORY COMMITTEEMEETING OF THE GENERAL HOSPITAL AND PERSONAL USE DEVICES PANELTransmissible Spongiform Encephalopathy (TSE)September 27, 2005Infection Control Devices BranchDivision of Anesthesiology, General Hospital, Infection Control and Dental DevicesCenter for Devices and Radiological Health

4. 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. HHS/FDA/CDRH

5. 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 HHS/FDA/CDRH

6. General Hospital and Personal Use Devices Panel • 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 HHS/FDA/CDRH

7. 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. HHS/FDA/CDRH

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

9. 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 HHS/FDA/CDRH

10. Iatrogenic Transmission of Creutzfeldt-Jakob disease Source # Incubation period Neurosurgery 4 17 months (12-28 m) EEG Electrodes 2 16-20 months Cornea Transplant 3 16-320 months Dura mater grafts 114 6 yrs (1.5 – 18 yrs) Growth Hormone 139 12 yrs ( 5-30 yrs) Gonadotropin 4 13 yrs ( 12-16 yrs) P Brown et al, Neurology 2000, 55:1075-1081 HHS/FDA/CDRH

11. Preventing Iatrogenic TSE Transmission by Contaminated Instruments • 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 HHS/FDA/CDRH

12. 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. • No cases of iatrogenic CJD resulting from these exposures have yet been reported. HHS/FDA/CDRH

13. Summary • TSEs are rare, fatal neurodegenerative diseases of man and animals • 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 • Is it possible to further reduce the risk? HHS/FDA/CDRH

14. 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 HHS/FDA/CDRH

15. In-Vivo Models for TSE Transmission HHS/FDA/CDRH

16. HHS/FDA/CDRH

17. Products/Processes which Reduce TSE Transmission Risk / Benefit Ratio HHS/FDA/CDRH

18. Products/Processes which Reduce TSE Transmission Benefit • Reduce the risk of transmission of Creutzfeldt-Jakob disease and other TSEs by contaminated surgical instruments HHS/FDA/CDRH

19. Products/Processes which Reduce TSE Transmission Risks • 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 HHS/FDA/CDRH

20. Products/Processes which Reduce TSE Transmission • 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? HHS/FDA/CDRH

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

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

24. Quantifying Benefit • Most common in prion literature: • Log reduction endpoint • Example: 6 log reduction endpoint • For every 1 million infectious particles (106)…..1 particle remains Before After 108/gm 102/gm • Used in virology and bacteriology HHS/FDA/CDRH

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

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. Goals • 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. HHS/FDA/CDRH

28. Annual Infection Risk [N x P] x [M x T] x 0.5 I [C x S] 0.25 infections/year HHS/FDA/CDRH

29. Parameter Value Ranges HHS/FDA/CDRH

30. Probabilistic Model Estimates of Annual Infection Rate(10,000 iterations) HHS/FDA/CDRH

31. 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. • 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. • Risk estimates may be used to determine magnitude of the risk and the effectiveness of risk reduction measures. HHS/FDA/CDRH

32. 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 HHS/FDA/CDRH

33. 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. HHS/FDA/CDRH

34. 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) • 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 HHS/FDA/CDRH

35. _______________PANEL QUESTIONS _______________ HHS/FDA/CDRH

36. Questions for the Advisory Panel • 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. HHS/FDA/CDRH

37. 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. HHS/FDA/CDRH

38. Questions for the Advisory Panel • Discuss the relevance of various design features of such validation studies. HHS/FDA/CDRH

39. 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 • Study population large enough for “sufficient statistical validity” • Log reduction in infectivity should be as large as possible HHS/FDA/CDRH

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

41. Questions for the Advisory Panel • 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? How may clinical benefit be estimated from these endpoints? HHS/FDA/CDRH

42. 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 stated that linking the mean incubation time to log reduction in infectivity could demonstrate clinical relevance HHS/FDA/CDRH

43. Questions for the Advisory Panel • 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? HHS/FDA/CDRH

44. 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 • testing different materials • testing simulated/surrogate device shapes HHS/FDA/CDRH

45. Questions for the Advisory Panel • 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? HHS/FDA/CDRH

46. 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. HHS/FDA/CDRH

47. Questions for the Advisory Panel • 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? HHS/FDA/CDRH

48. 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. HHS/FDA/CDRH