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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

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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

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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

general hospital and personal use devices panel
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

general hospital and personal use devices panel5
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

general hospital and personal use devices panel6
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

general hospital and personal use devices panel7
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

general hospital and personal use devices panel8
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

transmissible spongiform encephalopathy
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

iatrogenic transmission of creutzfeldt jakob disease
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

preventing iatrogenic tse transmission by contaminated instruments
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

preventing iatrogenic tse transmission by contaminated instruments12
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

summary
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

in vivo models of tse transmission
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

products processes which reduce tse transmission
Products/Processes which Reduce TSE Transmission

Risk / Benefit Ratio

HHS/FDA/CDRH

products processes which reduce tse transmission18
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

products processes which reduce tse transmission19
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

products processes which reduce tse transmission20
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

statistical considerations design and analysis

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

valid scientific evidence
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

properties of good experimental design
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

quantifying benefit
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

conclusions
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

iatrogenic cjd risk from reprocessed neurosurgical instruments

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

goals
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

annual infection risk
Annual Infection Risk

[N x P] x [M x T] x 0.5 I

[C x S]

0.25 infections/year

HHS/FDA/CDRH

probabilistic model estimates of annual infection rate 10 000 iterations
Probabilistic Model Estimates of Annual Infection Rate(10,000 iterations)

HHS/FDA/CDRH

risk characterization conclusions
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

general hospital and personal use devices panel32
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

mhra comments
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

mhra summary
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

panel questions
_______________PANEL QUESTIONS

_______________

HHS/FDA/CDRH

questions for the advisory panel
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

answers from the advisory panel
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

questions for the advisory panel38
Questions for the Advisory Panel
  • Discuss the relevance of various design features of such validation studies.

HHS/FDA/CDRH

answers from the advisory panel39
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

answers from the advisory panel40
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

questions for the advisory panel41
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

answers from the advisory panel42
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

questions for the advisory panel43
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

answers from the advisory panel44
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

questions for the advisory panel45
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

answers from the advisory panel46
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

questions for the advisory panel47
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

answers from the advisory panel48
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