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MEDICAL DEVICES ADVISORY COMMITTEEMEDICAL DEVICES ADVISORY COMMITTEEMEETING OF THE MEETING OF THE
GENERAL HOSPITAL AND PERSONAL USE GENERAL HOSPITAL AND PERSONAL USE DEVICES PANELDEVICES PANEL
Transmissible Spongiform Transmissible Spongiform Encephalopathy (TSE)Encephalopathy (TSE)
September 27, 2005September 27, 2005
Infection Control Devices BranchInfection Control Devices BranchDivision of Anesthesiology, General Hospital, Infection Control Division of Anesthesiology, General Hospital, Infection Control
and Dental Devicesand Dental DevicesCenter for Devices and Radiological HealthCenter for Devices and Radiological Health
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 33
Transmissible Spongiform Transmissible Spongiform EncephalopathyEncephalopathy
IntroductionIntroduction
Sheila A. Murphey, MDSheila A. Murphey, MD
Branch ChiefBranch ChiefInfection Control Devices BranchInfection Control Devices Branch
Division of Anesthesiology, General Hospital, Infection Control Division of Anesthesiology, General Hospital, Infection Control and Dental Devicesand Dental Devices
Center for Devices and Radiological HealthCenter for Devices and Radiological Health
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 44
General Hospital and Personal General Hospital and Personal Use Devices PanelUse Devices Panel
The Advisory Panel is asked to address The Advisory Panel is asked to address the scientific issues surrounding the the scientific issues surrounding the evaluation of products/processes evaluation of products/processes intended to reduce the bioburden of the intended to reduce the bioburden of the Creutzfeldt-Jakob transmissible agent on Creutzfeldt-Jakob transmissible agent on contaminated surgical instruments.contaminated surgical instruments.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 55
General Hospital and Personal General Hospital and Personal Use Devices PanelUse Devices Panel
In July 2003, DAGID asked the In July 2003, DAGID asked the Transmissible Spongiform Transmissible Spongiform Encephalopathies Advisory Encephalopathies Advisory Committee (TSEAC) to address the Committee (TSEAC) to address the issue of reprocessing medical issue of reprocessing medical devices contaminated or potentially devices contaminated or potentially contaminated by TSE agents.contaminated by TSE agents.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 66
General Hospital and personal General Hospital and personal Use Devices PanelUse Devices Panel
The questions on instrument The questions on instrument decontamination asked of TSEAC were decontamination asked of TSEAC were general and received general general and received general responses.responses.
TSEAC pointed out that little of the TSEAC pointed out that little of the experimental literature on TSE experimental literature on TSE inactivation is directly applicable to inactivation is directly applicable to hospital settings.hospital settings.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 77
General Hospital and Personal General Hospital and Personal Use Devices PanelUse Devices Panel
TSEAC stated that “there is no threshold TSEAC stated that “there is no threshold value below which exposure to a TSE value below which exposure to a TSE agent should be considered safe.agent should be considered safe.
TSEAC stated that “use of existing TSEAC stated that “use of existing methods cannot assure complete methods cannot assure complete removal of TSE agents from all materials removal of TSE agents from all materials under all circumstances”.under all circumstances”.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 88
General Hospital and Personal General Hospital and Personal Use Devices PanelUse Devices Panel
The Division of Anesthesiology, The Division of Anesthesiology, General Hospital, Infection Control General Hospital, Infection Control and Dental Devices (DAGID) believes and Dental Devices (DAGID) believes that it needs more guidance on the that it needs more guidance on the issues of TSE contamination of issues of TSE contamination of surgical instrumentssurgical instruments
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 99
General Hospital and Personal General Hospital and Personal Use Devices PanelUse Devices Panel
The number of scientific articles The number of scientific articles addressing the reduction/removal of TSE addressing the reduction/removal of TSE from instrument proxies is increasingfrom instrument proxies is increasing
Public interest in and concern about Public interest in and concern about variant Creutzfeldt-Jakob disease and its variant Creutzfeldt-Jakob disease and its potential for causing infections in the US potential for causing infections in the US is increasingis increasing
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 1010
General Hospital and Personal General Hospital and Personal Use Devices PanelUse Devices Panel
DAGID believes that it should DAGID believes that it should prepare for the possibility that prepare for the possibility that products or processes intended to products or processes intended to reduce TSE infectivity on surgical reduce TSE infectivity on surgical instruments will be submitted to FDA instruments will be submitted to FDA for premarket evaluation. for premarket evaluation.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 1111
General Hospital and Personal General Hospital and Personal Use Devices PanelUse Devices Panel
Presentations by FDAPresentations by FDA
Sheila A. Murphey, MDSheila A. Murphey, MD
Elaine S. Mayhall, PhDElaine S. Mayhall, PhD
Estelle Russek-Cohen, PhDEstelle Russek-Cohen, PhD
Ronald BrownRonald Brown
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 1212
General Hospital and Personal General Hospital and Personal Use Devices PanelUse Devices Panel
Guest SpeakerGuest Speaker
Allan HidderleyAllan HidderleySenior Medical Device SpecialistSenior Medical Device Specialist
Medicines and Healthcare Products Regulatory Medicines and Healthcare Products Regulatory Agency (Devices)Agency (Devices)
Device Technology and Safety-Biologics and Device Technology and Safety-Biologics and ImplantsImplants
United KingdomUnited Kingdom
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 1313
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 1414
Transmissible Spongiform Transmissible Spongiform EncephalopathyEncephalopathy
IntroductionIntroduction
Elaine Schalk Mayhall, Ph.D.Elaine Schalk Mayhall, Ph.D.
Infection Control Devices BranchInfection Control Devices Branch
Division of Anesthesiology, General Hospital, Infection Control Division of Anesthesiology, General Hospital, Infection Control and Dental Devicesand Dental Devices
Center for Devices and Radiological HealthCenter for Devices and Radiological Health
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 1515
Transmissible Spongiform Transmissible Spongiform EncephalopathyEncephalopathy
Transmissible spongiform Transmissible spongiform encephalopathies (TSE) are rare, encephalopathies (TSE) are rare, progressive neurodegenerative diseases progressive neurodegenerative diseases which affect both humans and animals.which affect both humans and animals.
TSEs result from the accumulation of the TSEs result from the accumulation of the abnormal isoform of a normal host cell abnormal isoform of a normal host cell protein which causes progressive neuronal protein which causes progressive neuronal dysfunction.dysfunction.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 1616
Human Transmissible Human Transmissible Spongiform Encephalopathies Spongiform Encephalopathies
IdiopathicIdiopathic - sporadic Creutzfeldt-Jakob Disease - sporadic Creutzfeldt-Jakob Disease (CJD)(CJD)
- sporadic fatal familial insomnia- sporadic fatal familial insomnia
Transmissible by Transmissible by IngestionIngestion
- variant CJD (from BSE)- variant CJD (from BSE)
- Kuru- Kuru
InheritedInherited - familial CJD- familial CJD
- familial fatal insomnia- familial fatal insomnia
- Gerstmann-Straussler-Scheinker - Gerstmann-Straussler-Scheinker SyndromeSyndrome
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 1717
Animal Transmissible Animal Transmissible Spongiform Encephalopathies Spongiform Encephalopathies
ScrapieScrapie SheepSheep
Bovine Spongiform Bovine Spongiform Encephalopathy (BSE)Encephalopathy (BSE)
Cattle (? from Scrapie)Cattle (? from Scrapie)
Transmissible Mink Transmissible Mink EncephalopathyEncephalopathy
Mink (? from Scrapie)Mink (? from Scrapie)
Feline Spongiform Feline Spongiform EncephalopathyEncephalopathy
Cats (from BSE) Cats (from BSE)
Exotic Ungulate Exotic Ungulate EncephalopathyEncephalopathy
Kudu, oryx, etc. (from Kudu, oryx, etc. (from BSE)BSE)
Chronic Wasting DiseaseChronic Wasting Disease Deer and ElkDeer and Elk
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 1818
Pathogenesis of Human Pathogenesis of Human Transmissible Spongiform Transmissible Spongiform
Encephalopathy Encephalopathy
PrPPrPc c Prion protein (cellular) - also called PrPPrion protein (cellular) - also called PrPsensen
Encoded by PRNP Encoded by PRNP Normal protein isoform, expressed on the surface Normal protein isoform, expressed on the surface
of neurons, glial cells, other cellsof neurons, glial cells, other cells Function uncertainFunction uncertain
PrionPrion stands for proteinaceous infectious stands for proteinaceous infectious particleparticle
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 1919
Pathogenesis of Human TSEPathogenesis of Human TSE
PrPPrPresres (PrP (PrPscsc))
Abnormal isoform of the normal prion Abnormal isoform of the normal prion protein, PrPprotein, PrP
Induces the conversion of PrPInduces the conversion of PrPcc to PrP to PrPresres
Accumulation of the abnormal isoform Accumulation of the abnormal isoform PrPPrPresres causes fatal neurodegenerative causes fatal neurodegenerative disease with a long incubation perioddisease with a long incubation period
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 2020
Pathogenesis of Human TSEPathogenesis of Human TSE
PrPPrPsensen PrPPrPres res
MonomerMonomer Oligomer or PolymerOligomer or Polymer
Sensitive to proteinase Sensitive to proteinase KK
Resistant to proteinase Resistant to proteinase KK
Cell surfaceCell surface VesiclesVesicles
Rapid synthesis and Rapid synthesis and degradationdegradation
Slow synthesis and Slow synthesis and degradationdegradation
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 2121
Pathogenesis of Human TSEPathogenesis of Human TSE
Conversion of PrPConversion of PrPsen sen to PrPto PrPres res
Acquisition of abnormal isoformAcquisition of abnormal isoform
““Sporadic” (Idiopathic) (?somatic mutation)Sporadic” (Idiopathic) (?somatic mutation) IngestionIngestion Iatrogenic transmission Iatrogenic transmission Inheritance of an abnormal isoform at least 30 Inheritance of an abnormal isoform at least 30
mutations describedmutations described
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 2222
Transmission of Human TSETransmission of Human TSE
When PrPWhen PrPresres is present, it can be is present, it can be transmitted to another hosttransmitted to another host
Transmission requires prion transfer, Transmission requires prion transfer, usually in tissue.usually in tissue.
While central nervous system (CNS) tissue While central nervous system (CNS) tissue is the most effective vehicle, other tissues is the most effective vehicle, other tissues can also transfer prionscan also transfer prions
Efficiency of transmission is dose-relatedEfficiency of transmission is dose-related
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 2323
Transmission of TSETransmission of TSE
Risk of TSE transmission will be Risk of TSE transmission will be determined bydetermined by
Availability of a TSE sourceAvailability of a TSE source Likely frequency of a “transmissible” Likely frequency of a “transmissible”
encounter with a TSE sourceencounter with a TSE source Effective TSE “dose”Effective TSE “dose” Larger doses are more efficient in Larger doses are more efficient in
transmissiontransmission
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 2424
Iatrogenic Transmission of Iatrogenic Transmission of Creutzfeldt-Jakob diseaseCreutzfeldt-Jakob disease
Source #Source # Incubation Incubation periodperiod
Neurosurgery 5Neurosurgery 5 17 months (12-28 m)17 months (12-28 m)EEG Electrodes 2 EEG Electrodes 2 16-20 months16-20 monthsCornea Transplant 3 Cornea Transplant 3 16-320 months16-320 monthsDura mater grafts 114Dura mater grafts 114 6 yrs (1.5 – 18 yrs)6 yrs (1.5 – 18 yrs)Growth Hormone 139Growth Hormone 139 12 yrs ( 5-30 yrs)12 yrs ( 5-30 yrs)Gonadotropin 4Gonadotropin 4 13 yrs ( 12-16 yrs)13 yrs ( 12-16 yrs)
P Brown et al, Neurology 2000, P Brown et al, Neurology 2000, 55:1075-108155:1075-1081
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 2525
Iatrogenic Transmission of CJD Iatrogenic Transmission of CJD by Contaminated Surgical by Contaminated Surgical
InstrumentsInstruments All 7 reported cases of CJD transmission by All 7 reported cases of CJD transmission by
contaminated surgical instruments/EEG contaminated surgical instruments/EEG electrodes occurred between 1954 and electrodes occurred between 1954 and 19801980
All 7 reported cases of CJD transmission by All 7 reported cases of CJD transmission by contaminated surgical instruments/EEG contaminated surgical instruments/EEG electrodes occurred in Europe (UK 4, electrodes occurred in Europe (UK 4, Switzerland 2, France 1)Switzerland 2, France 1)
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 2626
Preventing Iatrogenic TSE Preventing Iatrogenic TSE Transmission by Contaminated Transmission by Contaminated
InstrumentsInstruments
Human forms of TSE can be transmittedHuman forms of TSE can be transmitted
Transmission by materials and instruments Transmission by materials and instruments contaminated by CNS tissue from CJD contaminated by CNS tissue from CJD patients has occurredpatients has occurred
CJD patients are not always promptly CJD patients are not always promptly diagnosed in the early stages of diseasediagnosed in the early stages of disease
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 2727
Preventing Iatrogenic TSE Preventing Iatrogenic TSE Transmission by Contaminated Transmission by Contaminated
InstrumentsInstruments Currently Recommended Clinical PracticeCurrently Recommended Clinical Practice
Precautions to prevent the transmission of TSE by Precautions to prevent the transmission of TSE by contaminated surgical instruments should be contaminated surgical instruments should be taken for invasive CNS procedures in patients taken for invasive CNS procedures in patients with dementia of uncertain origin and patients with dementia of uncertain origin and patients known or suspected of having TSE.known or suspected of having TSE.
Precautions to prevent instrument transmission Precautions to prevent instrument transmission should also be taken for extraneural procedures should also be taken for extraneural procedures although the risk of transmission is lower.although the risk of transmission is lower.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 2828
Preventing Iatrogenic TSE Preventing Iatrogenic TSE Transmission by Contaminated Transmission by Contaminated
InstrumentsInstrumentsCurrently Recommended Clinical PracticeCurrently Recommended Clinical Practice
Surgical instruments may be discardedSurgical instruments may be discarded Surgical instruments may be quarantined Surgical instruments may be quarantined
until a diagnosis is confirmeduntil a diagnosis is confirmed Surgical instruments may be treated with Surgical instruments may be treated with
processes shown to have some in-vivo effect processes shown to have some in-vivo effect in reducing TSE transmission and in reducing TSE transmission and recommended by CDCrecommended by CDC
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 2929
Preventing Iatrogenic TSE Preventing Iatrogenic TSE Transmission by Contaminated Transmission by Contaminated
Surgical InstrumentsSurgical Instruments Studies at the National Institutes of Health Studies at the National Institutes of Health
have identified several methods of have identified several methods of instrument treatment which reduce TSE instrument treatment which reduce TSE transmission.transmission.
These have been recommended for clinical These have been recommended for clinical consideration by the CDC and other consideration by the CDC and other authorities.authorities.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 3030
Preventing Iatrogenic TSE Preventing Iatrogenic TSE Transmission by Contaminated Transmission by Contaminated
InstrumentsInstruments
Currently Recommended Clinical PracticeCurrently Recommended Clinical Practice
Prevacuum steam sterilization at 134Prevacuum steam sterilization at 13400C for 18 C for 18 minmin
Gravity steam sterilization at 121Gravity steam sterilization at 12100C for 1 hrC for 1 hr Immersion in 1 N NaOH for 1 hr Immersion in 1 N NaOH for 1 hr
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 3131
Preventing Iatrogenic TSE Preventing Iatrogenic TSE Transmission by Contaminated Transmission by Contaminated
InstrumentsInstruments
NaOH immersion and TSE sterilizer cycles NaOH immersion and TSE sterilizer cycles have been used togetherhave been used together
Sodium hypochlorite immersion has been Sodium hypochlorite immersion has been recommended by some authoritiesrecommended by some authorities
Currently recommended decontamination Currently recommended decontamination procedures are corrosive and unsuitable procedures are corrosive and unsuitable for heat-sensitive materialsfor heat-sensitive materials
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 3232
Preventing Iatrogenic TSE Preventing Iatrogenic TSE Transmission by Contaminated Transmission by Contaminated
InstrumentsInstruments
Currently recommended procedures Currently recommended procedures for treating CJD-contaminated for treating CJD-contaminated surgical instruments have not been surgical instruments have not been systematically studied for clinical systematically studied for clinical efficacyefficacy
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 3333
Preventing Iatrogenic TSE Preventing Iatrogenic TSE Transmission by Contaminated Transmission by Contaminated
InstrumentsInstruments
Iatrogenic transmission of CJD by CJD-Iatrogenic transmission of CJD by CJD-contaminated surgical instruments has not contaminated surgical instruments has not been reported since 1980been reported since 1980
Small epidemiologic studies of risk factors Small epidemiologic studies of risk factors for CJD have not consistently shown any for CJD have not consistently shown any statistically significant association statistically significant association between surgery and CJDbetween surgery and CJD
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 3434
Preventing Iatrogenic TSE Preventing Iatrogenic TSE Transmission by Contaminated Transmission by Contaminated
InstrumentsInstruments Exposures of patients to instruments used Exposures of patients to instruments used
in invasive CNS procedures on patients in invasive CNS procedures on patients with unrecognized CJD have been with unrecognized CJD have been reported.reported.
No cases of iatrogenic CJD resulting from No cases of iatrogenic CJD resulting from these exposures have yet been reported.these exposures have yet been reported.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 3535
Transmission of TSETransmission of TSE
Availability of a TSE Source in the USAvailability of a TSE Source in the US
““Sporadic” CJD is the most common TSE in Sporadic” CJD is the most common TSE in the USthe US
Average annual US death rate from CJD is Average annual US death rate from CJD is 0.95 per million persons0.95 per million persons
vCJD has been described only once in the vCJD has been described only once in the US in a recent UK emigrantUS in a recent UK emigrant
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 3636
Does vCJD Increase the Risk of Does vCJD Increase the Risk of Iatrogenic TSE transmission?Iatrogenic TSE transmission?
Patients with variant CJD (vCJD) have greater Patients with variant CJD (vCJD) have greater extra-neural tissue burdens of PrPextra-neural tissue burdens of PrPres res
Patients with vCJD may have atypical and Patients with vCJD may have atypical and prolonged symptoms before diagnosisprolonged symptoms before diagnosis
The number of patients with presymptomatic The number of patients with presymptomatic vCJD may be increasingvCJD may be increasing
There is concern that the risk of vCJD There is concern that the risk of vCJD transmission by surgical instruments may be transmission by surgical instruments may be increasing in areas affected by the BSE increasing in areas affected by the BSE epidemic and may involve other tissues epidemic and may involve other tissues besides CNS tissuesbesides CNS tissues
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 3737
SummarySummary TSEs are rare, fatal neurodegenerative TSEs are rare, fatal neurodegenerative
diseases of man and animalsdiseases of man and animals
TSE has, very rarely, been transmitted by TSE has, very rarely, been transmitted by contaminated surgical instrumentscontaminated surgical instruments
Current clinical practice based on the CDC Current clinical practice based on the CDC recommendations may reduce the risk of TSE recommendations may reduce the risk of TSE transmission by contaminated instrumentstransmission by contaminated instruments
Is it possible to further reduce the risk?Is it possible to further reduce the risk?
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 3838
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 3939
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Experimental Design IssuesExperimental Design Issues
Sheila A. Murphey, MDSheila A. Murphey, MD
Branch ChiefBranch ChiefInfection Control Devices BranchInfection Control Devices Branch
Division of Anesthesiology, General Hospital, Infection Control Division of Anesthesiology, General Hospital, Infection Control and Dental Devicesand Dental Devices
Center for Devices and Radiologic HealthCenter for Devices and Radiologic Health
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 4040
Experimental Methods for Experimental Methods for Studying TSEStudying TSE
MethodsMethods Can Examine Can Examine
TransmissibilitTransmissibilityy
Instrument Instrument ProxiesProxies
In-Vivo In-Vivo ModelsModels
YESYES YESYES
ImmunoassayImmunoassayss
NONO NONO
Cell CultureCell Culture NONO NONO
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 4141
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Prion sourcePrion source Susceptible host animalSusceptible host animal CNS introductionCNS introduction Observe host for symptoms of TSE or Observe host for symptoms of TSE or
sacrifice asymptomatic survivors at sacrifice asymptomatic survivors at predetermined endpointpredetermined endpoint
Confirm outcome by examination of CNS Confirm outcome by examination of CNS for evidence of TSE infectionfor evidence of TSE infection
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 4242
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmissionPrion SourcesPrion Sources
Human CJDHuman CJD - sporadic - sporadic
- variant- variant
- genetic- genetic ScrapieScrapie Bovine Spongiform Encephalopathy (BSE)Bovine Spongiform Encephalopathy (BSE) Other Animal PrionsOther Animal Prions
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 4343
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Most Common Hosts Most Common Hosts MiceMice HamstersHamsters Guinea PigGuinea Pig
Hosts may be genetically altered to carry Hosts may be genetically altered to carry other species’ PrPother species’ PrPc c
Host lifespan may differ from original host. Host lifespan may differ from original host. Will this affect the natural history of Will this affect the natural history of infection or the interpretation of results?infection or the interpretation of results?
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 4444
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Overcoming Species Barriers to TSE Overcoming Species Barriers to TSE TransmissionTransmission
Large infecting inoculumLarge infecting inoculum Serial passage in new hostSerial passage in new host Genetic manipulation of the host by Genetic manipulation of the host by
introducing a new PrPintroducing a new PrPsensen
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 4545
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Introduction of TSE Sources into CNSIntroduction of TSE Sources into CNS
Whole brain tissueWhole brain tissue Homogenates of brainHomogenates of brain Material may be dilutedMaterial may be diluted Material may be pooled from several Material may be pooled from several
sourcessources Material may have been frozen before Material may have been frozen before
useuse
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 4646
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Introduction of Inoculum into CNSIntroduction of Inoculum into CNS
Injection by needleInjection by needle Coated stainless steel wire – may be left Coated stainless steel wire – may be left
in-situ or removed after insertion in-situ or removed after insertion Coated stainless steel spheresCoated stainless steel spheres
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 4747
In-Vivo Models for TSE In-Vivo Models for TSE TransmissionTransmission
Experimental Experimental ModelModel
New steel needleNew steel needle
New stainless steel wireNew stainless steel wire
New stainless steel New stainless steel spheresspheres
Real InstrumentsReal Instruments
Aged, pitted surfaceAged, pitted surface
Steel, various metal Steel, various metal alloys, other materialsalloys, other materials
Complex shapesComplex shapes
Hard to clean Hard to clean areasareas Hinged surfaces Hinged surfaces Mated surfaces Mated surfaces LumensLumens
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 4848
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 4949
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 5050
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 5151
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Serial laboratory passage of prions Serial laboratory passage of prions may alter strain characteristicsmay alter strain characteristics AG Dickinson, DM Taylor NEJM 1978 AG Dickinson, DM Taylor NEJM 1978
229:1413-1414229:1413-1414 Scrapie strain inactivation at 126Scrapie strain inactivation at 12600 C C
Strain 139A 2 hrsStrain 139A 2 hrs Strain 22A 4 hrsStrain 22A 4 hrs
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 5252
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Sources of Variability in the Prion SourceSources 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 Inoculation of host animals on one day or
over several days?over several days? Has variation in the inoculum load on the Has variation in the inoculum load on the
wire been measured?wire been measured?
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 5353
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Sources of Variability in Host Sources of Variability in Host MaintenanceMaintenance
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 Intercurrent deaths must be considered in the statistical analysis of the resultsthe statistical analysis of the results
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 5454
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Confirmation of the CNS Status of TSE-Exposed Hosts 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 Jackson G,McKintosh E, Flechsig E et al. J Gen Virol 2005 86:869-8782005 86:869-878 ““While autoclaving appeared to be effective, histologic examination of While autoclaving appeared to be effective, histologic examination of
clinically unaffected animals revealed signs of infection in 2 of 6 clinically unaffected animals revealed signs of infection in 2 of 6 animals from the 121animals from the 12100C group and 1 of 4 animals from the 134C group and 1 of 4 animals from the 13400C C group”. group”.
This was also noted in 2 other experimental groups; 4 of 5 animals in 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 134the LpHse group and 1 of 5 in the Enzymes = autoclaved at 13400C C group.group.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 5555
In Vivo Models of TSE In Vivo Models of TSE TransmissionTransmission
Experimental models examine whether or Experimental models examine whether or not TSE is transmittednot TSE is transmitted
The presence or absence of TSE infection in The presence or absence of TSE infection in all experimental animals must be all experimental animals must be determineddetermined
Asymptomatic, sacrificed animals may have Asymptomatic, sacrificed animals may have TSE infectionTSE infection
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 5656
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
How closely does the experimental How closely does the experimental process reflect actual clinical process reflect actual clinical practice?practice?
Surgical instruments are normally cleaned, Surgical instruments are normally cleaned, packaged for sterilization and re-sterilized after packaged for sterilization and re-sterilized after each use. Will all of these steps be included in each use. Will all of these steps be included in the study intended to validate the use of a the study intended to validate the use of a product on surgical instruments? product on surgical instruments?
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 5757
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
How closely does the experimental How closely does the experimental process reflect actual clinical practice?process reflect actual clinical practice?
Will “cleaning” differ for 5mm wires Will “cleaning” differ for 5mm wires versus an instrument? Will technique, versus an instrument? Will technique, cleaning agents, temperature, etc. vary?cleaning agents, temperature, etc. vary?
Will “cleaning” a 5mm wire remove so Will “cleaning” a 5mm wire remove so much inoculum that the experimental much inoculum that the experimental outcome would be affected? How could outcome would be affected? How could removal be measured?removal be measured?
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 5858
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
How closely does the experimental How closely does the experimental process reflect actual clinical practice?process reflect actual clinical practice?
Will the 5mm wire be “packaged” for Will the 5mm wire be “packaged” for sterilization in the same way as an sterilization in the same way as an instrument? (Instruments may be placed instrument? (Instruments may be placed in wrapped trays or in sterilization in wrapped trays or in sterilization “pouches” before sterilization.)“pouches” before sterilization.)
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 5959
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
How closely does the experimental How closely does the experimental process reflect actual clinical process reflect actual clinical practice?practice?
Will cleaning be performed with standard Will cleaning be performed with standard products in clinical use?products in clinical use?
Will sterilizer cycles normally used in Will sterilizer cycles normally used in hospitals be included in the experimental hospitals be included in the experimental design?design?
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 6060
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Calculated Endpoints for TSE Calculated Endpoints for TSE TransmissionTransmission
Median Incubation PeriodMedian Incubation Period Median Survival Median Survival Percent Survival Percent Survival Log Reduction in InfectivityLog Reduction in Infectivity
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 6161
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Calculated endpoints for TSE Calculated endpoints for TSE TransmissionTransmission
The “control” curve is created by The “control” curve is created by administering serial dilutions of the administering serial dilutions of the untreated inoculum and observing the untreated inoculum and observing the outcomesoutcomes
The “experimental” group outcomes are The “experimental” group outcomes are compared to the “controls”compared to the “controls”
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 6262
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
As the TSE dose in the serial dilutions As the TSE dose in the serial dilutions of the untreated inoculum decreases.of the untreated inoculum decreases.
Median incubation period to symptoms Median incubation period to symptoms increasesincreases
Survival without infection begins to occur Survival without infection begins to occur below the IDbelow the ID100100 dose dose
At the IDAt the ID5050 dose, half of the exposed dose, half of the exposed animals will survive without infectionanimals will survive without infection
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 6363
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
““Log Reduction in Infectivity” as an EndpointLog Reduction in Infectivity” as an Endpoint
Magnitude of CNS infection varies (10Magnitude of CNS infection varies (1077 to 10 to 1011 11
LDLD5050/g brain) by model system (Prion/Host) /g brain) by model system (Prion/Host) Magnitude of the possible reduction can vary Magnitude of the possible reduction can vary
by model systemby model system ““Measurement” requires comparison to the Measurement” requires comparison to the
“dilution curve”“dilution curve”
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 6464
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
““Log Reduction in Infectivity” as an Log Reduction in Infectivity” as an EndpointEndpoint
Exact measurement of the CNS inoculum Exact measurement of the CNS inoculum on a wire is difficulton a wire is difficult
““Reduction” is measured from the infecting Reduction” is measured from the infecting dose on the wire to the estimated survival dose on the wire to the estimated survival endpoint of the hostendpoint of the host
Lower limit of detection for these models Lower limit of detection for these models has not been determinedhas not been determined
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 6565
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Evaluation of Experimental ResultsEvaluation of Experimental Results
Is there a measurable difference between Is there a measurable difference between the experimental and control groups?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?
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 6666
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Evaluation of Experimental ResultsEvaluation of Experimental Results
Is the experimental differenceIs the experimental difference
Statistically Significant?Statistically Significant?
Clinically Significant?Clinically Significant?
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 6767
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Evaluation of Experimental ResultsEvaluation of Experimental Results
Different model systems will produce Different model systems will produce different results. different results.
Different prion characteristics such as Different prion characteristics such as
sensitivity to heat inactivation.sensitivity to heat inactivation. Different magnitude of infection.Different magnitude of infection.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 6868
In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission
Are in-vivo experimental model of Are in-vivo experimental model of TSE transmission results clinically TSE transmission results clinically relevant?relevant?
Should current clinical practice be Should current clinical practice be altered on the basis of such altered on the basis of such experimental results?experimental results?
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 6969
Products/Processes which Products/Processes which Reduce TSE TransmissionReduce TSE Transmission
Risk / Benefit RatioRisk / Benefit Ratio
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 7070
Products/Processes which Products/Processes which Reduce TSE TransmissionReduce TSE Transmission
BenefitBenefit
Reduce the risk of transmission of Reduce the risk of transmission of Creutzfeldt-Jakob disease and other Creutzfeldt-Jakob disease and other TSEs by contaminated surgical TSEs by contaminated surgical instrumentsinstruments
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 7171
Products/Processes which Products/Processes which Reduce TSE TransmissionReduce TSE Transmission
RisksRisks
False sense of security about the risk of False sense of security about the risk of transmitting TSE by contaminated transmitting TSE by contaminated instrumentsinstruments
Failure to adequately follow practices Failure to adequately follow practices currently recommended to reduce the risk currently recommended to reduce the risk of TSE transmission by contaminated of TSE transmission by contaminated instrumentsinstruments
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 7272
Products/Processes which Products/Processes which Reduce TSE TransmissionReduce TSE Transmission
RisksRisks Less attention to identifying patients with Less attention to identifying patients with
possible CJD before invasive procedures, possible CJD before invasive procedures, especially neurosurgeryespecially neurosurgery
Less attention to quarantining, discarding Less attention to quarantining, discarding or specially processing instruments used or specially processing instruments used in invasive procedures on patients with in invasive procedures on patients with possible or definite CJDpossible or definite CJD
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 7373
Products/Processes which Products/Processes which Reduce TSE TransmissionReduce TSE Transmission
RisksRisks Less attention to carefully cleaning Less attention to carefully cleaning
contaminated surgical instrumentscontaminated surgical instruments Less willingness to follow current CDC Less willingness to follow current CDC
recommendations for handling instruments recommendations for handling instruments possibly contaminated by CJDpossibly contaminated by CJD
Less willingness to discard hard-to-clean Less willingness to discard hard-to-clean contaminated instruments possibly contaminated instruments possibly contaminated by CJDcontaminated by CJD
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 7474
Products/Processes which Products/Processes which Reduce TSE TransmissionReduce TSE Transmission
Is the clinical benefit of approving Is the clinical benefit of approving potential products/processes which potential products/processes which reduce TSE transmission from its reduce TSE transmission from its current level significant?current level significant?
Does this benefit outweigh the Does this benefit outweigh the possible risks?possible risks?
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 7575
Statistical Considerations:Statistical Considerations:Design and AnalysisDesign and Analysis
Estelle Russek-Cohen, Ph.D. Estelle Russek-Cohen, Ph.D.
Team LeaderTeam LeaderDivision of BiostatisticsDivision of Biostatistics
Center for Devices and Radiological Center for Devices and Radiological HealthHealth
Food and Drug AdministrationFood and Drug Administration
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 7777
OutlineOutline
BackgroundBackground Key components to Study DesignsKey components to Study Designs Log reduction endpointLog reduction endpoint Improving survival or time to first Improving survival or time to first
symptomssymptoms Data analysis Issues Data analysis Issues ConclusionsConclusions
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 7878
Valid Scientific EvidenceValid Scientific Evidence
Studies presented must support Studies presented must support intended use claimintended use claim
Study requirements:Study requirements: Product must be tested to support Product must be tested to support
labeling instructionslabeling instructions Conclusions must have a degree of Conclusions must have a degree of
confidence (e.g. statistical confidence (e.g. statistical significance)significance)
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 7979
Previously Published PapersPreviously Published Papers
1-3 cages of animals per treatment1-3 cages of animals per treatment 4-12 animals per treatment4-12 animals per treatment Single source of TSE-infected brain Single source of TSE-infected brain
materialmaterial 1 to 5 brains used 1 to 5 brains used
Infected homogenate or Infected homogenate or infected wireinfected wire 1-2 batches of “cleaner”1-2 batches of “cleaner” All in controlled research environment All in controlled research environment
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 8080
Key Components to Study Key Components to Study DesignDesign
Lengthy incubation period:Lengthy incubation period: 1-2 year study is needed1-2 year study is needed
On each animal can record:On each animal can record: Survives (Y/N) beyond fixed time periodSurvives (Y/N) beyond fixed time period
Percent survivalPercent survival less efficient statisticallyless efficient statistically
Time until death or (??) symptomsTime until death or (??) symptoms**
Median survivalMedian survival
**Can consider competing causes of deathCan consider competing causes of death
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 8181
Competing Causes of DeathCompeting Causes of Death
Ignoring competing causes of death Ignoring competing causes of death introduces bias.introduces bias.
If animal dies, we expect it will be If animal dies, we expect it will be necropsied. necropsied.
If animal has prion disease at time of If animal has prion disease at time of death but death is not due to prion death but death is not due to prion disease, we can consider it as a death due disease, we can consider it as a death due to to prion disease.to to prion disease.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 8282
LimitationsLimitations
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 How does it depend on animal model
and type of TSE?and type of TSE? Relevance to humans?Relevance to humans?
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 8383
““Extraneous” Variables Extraneous” Variables
TechnicianTechnician Animal to animal variationAnimal to animal variation
Housing 4-5 animals/cageHousing 4-5 animals/cage
Cages are in batteries Cages are in batteries Variation in strength of initial Variation in strength of initial
inoculateinoculate Lot-to-lot variation in productLot-to-lot variation in product
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 8484
A Cage Battery A Cage Battery
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 8585
Properties of good Properties of good experimental designexperimental design
Absence of systematic errorAbsence of systematic error Precision of endpoint Precision of endpoint Range of validityRange of validity SimplicitySimplicity
Calculation of uncertaintyCalculation of uncertainty D.R. Cox: Planning of Experiments D.R. Cox: Planning of Experiments
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 8686
Properties of good Properties of good experimental designexperimental design
Absence of systematic errorAbsence of systematic error Reduce bias Reduce bias Precision of endpoint Precision of endpoint Time to death rather than yes or noTime to death rather than yes or no Range of validityRange of validity Do “extraneous variables” impact performance?Do “extraneous variables” impact performance? SimplicitySimplicity Calculation of uncertaintyCalculation of uncertainty Reporting confidence intervals or levels of Reporting confidence intervals or levels of
significance significance D.R. Cox: Planning of Experiments D.R. Cox: Planning of Experiments
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 8787
Components of Good Study Components of Good Study Design Design
Reduce bias via randomization:Reduce bias via randomization: Randomization of animals to cages and Randomization of animals to cages and
then randomize cages to treatmentsthen randomize cages to treatments Randomization of order in which Randomization of order in which
treatment is administeredtreatment is administered
Concurrent application of all Concurrent application of all experimental and control group(s)experimental and control group(s)
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 8888
Experimental UnitExperimental Unit
Each cage is randomized to a single Each cage is randomized to a single treatment, thus each cage is an treatment, thus each cage is an experimental unit. experimental unit.
Observations within cage are Observations within cage are not not independentindependent
This is not just because:This is not just because: Disease is infectiousDisease is infectious
Analysis must reflect this:Analysis must reflect this: Standard for Veterinary submissions at FDA Standard for Veterinary submissions at FDA
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 8989
Quantifying BenefitQuantifying Benefit
Most common in prion literature:Most common in prion literature: Log reduction endpointLog reduction endpoint
Example: 6 log reduction endpointExample: 6 log reduction endpoint For every 1 million infectious particles For every 1 million infectious particles
(10(1066)…..1 particle remains)…..1 particle remains
Before AfterBefore After 101088/gm 10/gm 1022/gm/gm Used in virology and bacteriologyUsed in virology and bacteriology
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 9090
Controls: Log Reduction Controls: Log Reduction Endpoint (no cleaning or Endpoint (no cleaning or
disinfection)disinfection) Controls: to establish a standard curveControls: to establish a standard curve Controls: animals exposed to varying Controls: animals exposed to varying
levels of infected materiallevels of infected material TSE infected inoculate is diluted in a TSE infected inoculate is diluted in a
series of 10-fold dilutions (.1, .01, .001,series of 10-fold dilutions (.1, .01, .001,…)…)
How is dilution prepared and how does How is dilution prepared and how does it impact sticking to wire?it impact sticking to wire?
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 9191
Treatment Using ProductTreatment Using Product
Use undiluted homogenate to infect wireUse undiluted homogenate to infect wire Apply product to disinfect Apply product to disinfect as on labelas on label As in controls, use wires to infect clean As in controls, use wires to infect clean
animalsanimals Calculate outcomes as in controlsCalculate outcomes as in controls See which dilution level it compares toSee which dilution level it compares to
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 9292
Hypothetical DataHypothetical 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 => 1010% => .10 => 10-1-1
Assume enough animals for each dilution Assume enough animals for each dilution level to reasonably estimate percent level to reasonably estimate percent survivalsurvival
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 9393
Estimating Log ReductionEstimating Log ReductionHypothetical exampleHypothetical example
1 2 3 4 5 6 7 8 9
Dilution Level
0.0
0.2
0.4
0.6
0.8
1.0
Sur
viva
lR
ate
Test Group
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 9494
Limitations of Log Reduction Limitations of Log Reduction StudyStudy
Complex design issues with log reduction endpointComplex design issues with log reduction endpoint
Large numbers of controlsLarge numbers of controls Each dilution level =group of animalsEach dilution level =group of animals
i.e. 9 dilutions= 9 groupsi.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 Indirect endpoint: one assumes log reduction does not depend on size of initial inoculateon size of initial inoculate
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 9595
Single “Disinfectant” Group Single “Disinfectant” Group Single Control Group Single Control Group
No log reduction endpointNo log reduction endpoint Uses standard operating procedure with Uses standard operating procedure with
untreated homogenate+wireuntreated homogenate+wire Still measure either: Still measure either:
Survival (Y/N)Survival (Y/N) Time until death or onset of symptomsTime until death or onset of symptoms
Simpler design: easier to control Simpler design: easier to control extraneous factors extraneous factors
Analysis and sample size needs are Analysis and sample size needs are simpler to determinesimpler to determine
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 9696
Repeat Experiment Over Repeat Experiment Over TimeTime
Not all animals have to be done at onceNot 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 timeAll treatments appear at each time New lot of product at each timeNew lot of product at each time New batch of inoculate at each timeNew batch of inoculate at each time New cage batteries at each timeNew cage batteries at each time Animals can be of comparable agesAnimals can be of comparable ages
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 9797
Advantages: Replicating Over Advantages: Replicating Over TimeTime
Assesses overall reproducibility of Assesses overall reproducibility of studystudy
With both log reduction study and With both log reduction study and two group study: there will be two group study: there will be variation in initial inoculate variation in initial inoculate
Reproducibility in time is a Reproducibility in time is a compromise because reproducibility compromise because reproducibility over sites is not feasible. over sites is not feasible.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 9898
Data AnalysisData Analysis
Many journal articles do NOT present Many journal articles do NOT present formal statistical analyses formal statistical analyses (e.g. no 95% confidence intervals)(e.g. no 95% confidence intervals)
Valid scientific evidence requires an Valid scientific evidence requires an appropriate statistical analysisappropriate statistical analysis
Analysis should be consistent with Analysis should be consistent with study designstudy design
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 9999
Sample Sizes: Simple Sample Sizes: Simple DesignDesign
Consider case of two groups:Consider case of two groups: One control and one disinfectantOne control and one disinfectant
Consider a binary endpoint:Consider a binary endpoint: Animal dies or does not die of diseaseAnimal dies or does not die of disease
Enough control animals to establish Enough control animals to establish inoculate is sufficiently deadlyinoculate is sufficiently deadly
Enough treatment animals to say at Enough treatment animals to say at least 99% will survive disease least 99% will survive disease
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 100100
The NumbersThe Numbers
2 cages of animals at each time point to 2 cages of animals at each time point to establish inoculate is sufficiently establish inoculate is sufficiently infectiousinfectious EXPECT 100% MORTALITYEXPECT 100% MORTALITY
In treatment group: In treatment group: EXPECT 100% SURVIVALEXPECT 100% SURVIVAL
Lower 95% confidence bound >99%Lower 95% confidence bound >99% Need 1-3/N>.99 or 300 AnimalsNeed 1-3/N>.99 or 300 Animals
This ignores cage effect. This ignores cage effect.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 101101
Precision of survival estimatesPrecision of survival estimates75 cages with 4 animals75 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 If within cage effects are veryvery strong, strong, e.g. all animals die w/in cage or none e.g. all animals die w/in cage or none diedie Confidence bound is determined by: Confidence bound is determined by:
number of cages…not number animalsnumber of cages…not number animals 95% CI: (83.4%, 97.0%) 95% CI: (83.4%, 97.0%)
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 102102
95% Lower Confidence Bound: 95% Lower Confidence Bound: Observe 100% survivalObserve 100% survivalDepends on number of animals:Depends on number of animals:
NumberNumber IndependenceIndependence Complete Complete DependenceDependence
1212 77.9%77.9% 36.8%36.8%
3636 92.0%92.0% 71.7%71.7%
9696 96.9%96.9% 88.3%88.3%
200200 98.5%98.5% 94.2%94.2%
300300 99.0%99.0% 96.1%96.1%
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 103103
Time to event data: Survival or Time to event data: Survival or time to onset of symptomstime 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 causesMedian survival due to competing causes Median survival in control group or groups in case of Median survival in control group or groups in case of
log reduction endpointlog reduction endpoint Median survival in group treated with product would Median survival in group treated with product would
be neededbe needed
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 104104
Same considerationsSame 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 If competing causes are frequent, need
bigger Nbigger N
Statistical efficiency is driven by number of Statistical efficiency is driven by number of deaths due to prion disease. deaths due to prion disease.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 105105
ConclusionsConclusions
Details of a specific design will vary with Details of a specific design will vary with experimental modelexperimental model
Key sources of variation need to be Key sources of variation need to be considered in design and analysisconsidered in design and analysis
Design should consider experimental unitsDesign should consider experimental units Study must be sized sufficiently to Study must be sized sufficiently to
establish product effectiveness with an establish product effectiveness with an appropriate level of certaintyappropriate level of certainty
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 106106
Iatrogenic CJD Risk from Iatrogenic CJD Risk from Reprocessed Neurosurgical Reprocessed Neurosurgical
InstrumentsInstruments
Ron BrownRon Brown
LeaderLeaderLaboratory of Biological Risk AssessmentLaboratory of Biological Risk Assessment
Office of Science and Engineering LaboratoriesOffice of Science and Engineering LaboratoriesCenter for Devices and Radiological HealthCenter for Devices and Radiological Health
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 108108
GoalsGoals
Assess the annual risk of iatrogenic Assess the annual risk of iatrogenic CJD in the US in patients undergoing CJD in the US in patients undergoing neurosurgery with reprocessed neurosurgery with reprocessed neurosurgical instruments.neurosurgical instruments.
Does not address risk of iatrogenic CJD Does not address risk of iatrogenic CJD from instruments used at extraneural from instruments used at extraneural sites.sites.
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 109109
OverviewOverview Provide overview of modeling approaches to Provide overview of modeling approaches to
estimate riskestimate risk
Provide justification for parameter values used in the Provide justification for parameter values used in the modelsmodels
Underscore uncertainty associated with parameter Underscore uncertainty associated with parameter valuesvalues
Assess impact of parameter values on estimated riskAssess impact of parameter values on estimated risk
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 110110
Risk of TSE transmissionRisk of TSE transmission
Likely frequency of a “transmissible” Likely frequency of a “transmissible” encounter (probability of exposure)encounter (probability of exposure)
Availability of a TSE source (amount Availability of a TSE source (amount of TSE agent to which the patient is of TSE agent to which the patient is exposed)exposed)
Effective TSE dose (infectivity)Effective TSE dose (infectivity)
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 111111
Risk Assessment ParadigmRisk Assessment ParadigmNAS/NRC (1983)NAS/NRC (1983)
Hazard IdentificationHazard Identification Can CJD-infected CNS tissue serve as a source of iatrogenic Can CJD-infected CNS tissue serve as a source of iatrogenic
transmission of CJD?transmission of CJD?
Exposure AssessmentExposure AssessmentWhat is the dose of infected material transferred to the patient?What is the dose of infected material transferred to the patient?
Dose-Response AssessmentDose-Response AssessmentWhat is the relationship between the dose of TSE-contaminated What is the relationship between the dose of TSE-contaminated material and the incidence of infection?material and the incidence of infection?
Risk CharacterizationRisk CharacterizationWhat is the risk posed by exposure to TSE-contaminated What is the risk posed by exposure to TSE-contaminated
material?material?
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 112112
Hazard IdentificationHazard Identification
Widely understood that the abnormal form Widely understood that the abnormal form of prion protein is the etiologic agent for of prion protein is the etiologic agent for CJD in humans.CJD in humans.
Iatrogenic transmission of CJD is rare, but Iatrogenic transmission of CJD is rare, but has been reported following the use of has been reported following the use of contaminated depth EEG electrodes contaminated depth EEG electrodes (Bernoulli et al., 1977), dura mater grafts (Bernoulli et al., 1977), dura mater grafts (CDC, 2003) and neurosurgical (CDC, 2003) and neurosurgical instruments (Brown et al. 2000). instruments (Brown et al. 2000).
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 113113
Exposure AssessmentExposure AssessmentProbability of exposureProbability of exposure
Number of neurosurgeries performed Number of neurosurgeries performed annually in US (N)annually in US (N)
Proportion of the population that is Proportion of the population that is infected with CJD (P)infected with CJD (P)
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 114114
Exposure AssessmentExposure AssessmentDose to patientDose to patient
Total mass of tissue remaining on surgical Total mass of tissue remaining on surgical instruments after use (M)instruments after use (M)
Transfer of material from instruments to Transfer of material from instruments to patients (T)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)
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 115115
Dose-Response AssessmentDose-Response Assessment
Infectivity of the tissue transferred to the patient (I), Infectivity of the tissue transferred to the patient (I), represented as an intercerebral ID50.represented as an intercerebral ID50.
AssumptionsAssumptions Linear dose-response assessmentLinear dose-response assessment
All exposed individuals are vulnerable to infection, All exposed individuals are vulnerable to infection, genetic variations only affect incubation period.genetic variations only affect incubation period.
Similar dose-response relationship in Similar dose-response relationship in experimental animals and humansexperimental animals and humans
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 116116
Annual Infection RiskAnnual Infection Risk
[N x P] x [M x T] x 0.5 I[N x P] x [M x T] x 0.5 I[C x S][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)
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 117117
Models UsedModels UsedDeterministicDeterministic
Uses point estimates for input Uses point estimates for input parametersparameters
See only one solution at a timeSee only one solution at a time Ask “what if” questionsAsk “what if” questions Annual infection risk equation in ExcelAnnual infection risk equation in Excel Default parameter valuesDefault parameter values
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 118118
Models UsedModels UsedProbabilisticProbabilistic
Monte Carlo method Monte Carlo method
Repeatedly samples values from the probability Repeatedly samples values from the probability distributions for the variablesdistributions for the variables
Allows examination of aggregate uncertainties Allows examination of aggregate uncertainties and to derive risk ranges.and to derive risk ranges.
RiskAmp Monte Carlo add-in for ExcelRiskAmp Monte Carlo add-in for Excel
September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 119119
Number of Neurosurgical Number of Neurosurgical Procedures (N)Procedures (N)
CDC data (1996)CDC data (1996)
104,000 surgeries involving skull, brain104,000 surgeries involving skull, brain
and cerebral meningesand cerebral meninges Barker and Anim-Hanjani (2004)Barker and Anim-Hanjani (2004)
Craniotomy data; 70,800 – 1988; 105,300 – Craniotomy data; 70,800 – 1988; 105,300 – 2001 4% increase/year2001 4% increase/year
Default value: 125,000 neurosurgeries in 2005Default value: 125,000 neurosurgeries in 2005
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Proportion of Neurosurgeries Proportion of Neurosurgeries Conducted on Patients with Conducted on Patients with
sCJD (P)sCJD (P) Annual incidence of sCJD (not vCJD) in US Annual incidence of sCJD (not vCJD) in US
population: 1 in 1 million (1 x population: 1 in 1 million (1 x 1010-6-6))
Prevalence of subclinical disease is Prevalence of subclinical disease is unknown. Assume background rate of unknown. Assume background rate of asymptomatic CJD is higherasymptomatic CJD is higher
Default value: 2 x 10Default value: 2 x 10-6 -6
Range 1-10 x 10Range 1-10 x 10-6 -6
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Tissue Mass on Instruments (M)Tissue Mass on Instruments (M)
Assumptions from UK DOH (2001) risk Assumptions from UK DOH (2001) risk assessment of vCJD. Expert judgement assessment of vCJD. Expert judgement from panel.from panel.
10 mg of tissue on instruments after use10 mg of tissue on instruments after use 20 instruments/procedure20 instruments/procedure
Default Value:Default Value:1 x 10-2 g tissue/instrument x 20 instruments = 0.2 g tissue; 1 x 10-2 g tissue/instrument x 20 instruments = 0.2 g tissue;
Range 0.1 – 0.5 g tissueRange 0.1 – 0.5 g tissue
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Transfer of Tissue to Patients (T)Transfer of Tissue to Patients (T)
Range used in UK DOH (2001) risk Range used in UK DOH (2001) risk assessment: 0.0001 - 1assessment: 0.0001 - 1
Default assumption used in UK DOH Default assumption used in UK DOH (2001) risk assessment: 10% of (2001) risk assessment: 10% of material transferred upon reuse. material transferred upon reuse.
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Routine Cleaning EfficiencyRoutine Cleaning EfficiencyAlfa et al. (1999)Alfa et al. (1999)
DeviceDevice
LogLog1010 reduction reduction
in protein in protein contaminationcontamination
LogLog1010 reduction reduction
in microbial in microbial contaminationcontamination
BronchoscopeBronchoscope 0.660.66 1.851.85
DuodenoscopDuodenoscopee
0.990.99 2.052.05
ColonoscopeColonoscope 1.621.62 4.194.19
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Routine Cleaning EfficiencyRoutine Cleaning Efficiency
Verjat et al. (1999) Washing with Verjat et al. (1999) Washing with detergents reduces proteins on flat detergents reduces proteins on flat surfaces by 5 logssurfaces by 5 logs
Smith et al. (in press) Residual protein Smith et al. (in press) Residual protein on dental instruments – mean 5.4 ug.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 logDefault 2 log reduction, range 1-5 log
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Routine Sterilization EfficacyRoutine Sterilization Efficacy
Assumption used in UK DOH (2001) Assumption used in UK DOH (2001) risk assessment: Sterilization reduces risk assessment: Sterilization reduces infectivity of prion protein by 3-6 infectivity of prion protein by 3-6 logs.logs.
Similar range of values used in this Similar range of values used in this risk assessment. Default = 4 log risk assessment. Default = 4 log reductionreduction
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Cleaning and Sterilization Cleaning and Sterilization EfficiencyEfficiency
Default assumptionsDefault assumptions
Cleaning: 2 logCleaning: 2 log1010 reductions in infectivity reductions in infectivity
Sterilization: 4 logSterilization: 4 log1010 reductions in reductions in
infectivityinfectivity
Product of C x S = 1 x 10Product of C x S = 1 x 1066
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Tissue Infectivity (I)Tissue Infectivity (I) UK DOH (2001) risk assessment assumed value UK DOH (2001) risk assessment assumed value
of 10of 108 8 ic ID50/g brain tissue for subclinical ic ID50/g brain tissue for subclinical disease.disease.
Based on unpublished studies of tissues from Based on unpublished studies of tissues from deceased vCJD patients (Bruce, 2000 cited in deceased vCJD patients (Bruce, 2000 cited in UK DOH, 2001) and the data on experimental UK DOH, 2001) and the data on experimental scrapie in mice reported by Kimerberlin and scrapie in mice reported by Kimerberlin and Walker (1979).Walker (1979).
No stratification for ageNo stratification for age
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Annual Infection RiskAnnual Infection Risk
[N x P] x [M x T] x 0.5 I[N x P] x [M x T] x 0.5 I
[C x S][C x S]
0.25 infections/year0.25 infections/year
ParameterParameter Default Default ValueValue
NN 1.25 x 101.25 x 1055
PP 2 x 102 x 10-6-6
MM 2 x 102 x 10-1-1
TT 1 x 101 x 10-1-1
II 1 x 101 x 1088
CC 1 x 101 x 1022
SS 1 x 101 x 1044
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Deterministic ModelDeterministic ModelEvaluation of various scenariosEvaluation of various scenarios
Effectiveness of Routine Effectiveness of Routine Cleaning/SterilizationCleaning/Sterilization
Log reduction in infectivity Log reduction in infectivity
Infectivity of tissue (ID50)Infectivity of tissue (ID50)
101077 101088 101099
44 2.52.5 2525 250250
55 0.250.25 2.52.5 2525
66 0.0250.025 0.250.25 2.52.5
77 0.00250.0025 0.0250.025 0.250.25
88 0.000250.00025 0.00250.0025 0.0250.025
99 0.0000250.000025 0.000250.00025 0.00250.0025
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Probabilistic ModelProbabilistic ModelDistribution typesDistribution types
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ParameterParameter Lower-bound Lower-bound estimateestimate
Default estimateDefault estimate Upper-bound Upper-bound estimateestimate
Number of Number of neurosurgeries/neurosurgeries/year in US (N)year in US (N)
1 x 101 x 1055 1.25 x 101.25 x 1055 1.5 x 101.5 x 1055
Incidence of Incidence of infection in the infection in the population (P)population (P)
1 x 101 x 10-6-6 2 x 102 x 10-6-6 1 x 101 x 10-5-5
Mass of residual Mass of residual tissue (M) tissue (M) 0.10.1 0.20.2 0.50.5
Transfer of tissue Transfer of tissue to patient (T) to patient (T) 0.00010.0001 0.10.1 1.01.0
Infectivity (I)Infectivity (I) 1 x 101 x 1077 1 x 101 x 1088 1 x 101 x 1099
Cleaning efficiency Cleaning efficiency 1 x 101 x 1011 1 x 101 x 1022 1 x 101 x 1055
Sterilization Sterilization efficiency (S)efficiency (S) 1 x 101 x 1033 1 x 101 x 1044 1 x 101 x 1066
Parameter Value RangesParameter Value Ranges
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Probabilistic Model Estimates Probabilistic Model Estimates of Annual Infection Rateof Annual Infection Rate
(10,000 iterations(10,000 iterations))
Upper-bound estimate of the Upper-bound estimate of the background rate of asymptomatic background rate of asymptomatic
CJD = 1 x 10CJD = 1 x 10-5-5
Estimated infections/year Estimated infections/year in USin US
MeanMean 0.010.01
Percentile distributionPercentile distribution
55 0.0000490.000049
2525 0.0002650.000265
5050 0.0008680.000868
7575 0.0031550.003155
9595 0.0270900.027090
100100 3.5643.564
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Risk Characterization/ConclusionsRisk Characterization/Conclusions
Based on the assumptions used in the risk assessment, Based on the assumptions used in the risk assessment, the estimated annual iatrogenic CJD infection risk in US the estimated annual iatrogenic CJD infection risk in US from use of reprocessed neurosurgical instruments: from use of reprocessed neurosurgical instruments: < 1 infection/year.< 1 infection/year.
Estimates were derived using deterministic and Estimates were derived using deterministic and probabilistic approaches. Both approaches allow probabilistic approaches. Both approaches allow examination of risk under differing model assumptions.examination of risk under differing model assumptions.
Uncertainty associated with parameter estimates and Uncertainty associated with parameter estimates and final risk estimates.final risk estimates.
Risk estimates may be used to determine magnitude of Risk estimates may be used to determine magnitude of the risk and the effectiveness of risk reduction measures.the risk and the effectiveness of risk reduction measures.
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September 27, 2005September 27, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 135135
_______________PANEL QUESTIONS_______________
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Questions for the Advisory Questions for the Advisory PanelPanel
1.1. Assuming that a product sponsor Assuming that a product sponsor seeks a claim for “Reducing TSE seeks a claim for “Reducing TSE Infectivity” on stainless steel Infectivity” on stainless steel instruments, is it reasonable for such instruments, is it reasonable for such an indication to be validated using an indication to be validated using animal studies of TSE transmission? animal studies of TSE transmission? Please discuss.Please discuss.
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Questions for the Advisory Questions for the Advisory PanelPanel
2.2. Discuss the relevance of various Discuss the relevance of various design features of such validation design features of such validation studies.studies.
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Questions for the Advisory Questions for the Advisory PanelPanel
3.3. Of the 3 study endpoints cited in the Of the 3 study endpoints cited in the literature – log reduction in infectivity, literature – log reduction in infectivity, mean incubation time and survival mean incubation time and survival (median survival and percent survival), (median survival and percent survival), which, if any, may be adequate for the which, if any, may be adequate for the validation of a “Reducing TSE Infectivity” validation of a “Reducing TSE Infectivity” indication? indication?
Should demonstration of a particular Should demonstration of a particular level of reduction of TSE infectivity in one level of reduction of TSE infectivity in one or more endpoints be expected in order or more endpoints be expected in order to support a indication for use?to support a indication for use?
How may clinical benefit be estimated How may clinical benefit be estimated from these endpoints?from these endpoints?
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Questions for the Advisory Questions for the Advisory PanelPanel
4.4. What additional issues should be What additional issues should be considered by FDA when evaluating considered by FDA when evaluating indications for use for devices other than indications for use for devices other than simple surgical steel instruments? simple surgical steel instruments?
How can devices constructed from or How can devices constructed from or including materials other than stainless including materials other than stainless steel, devices with complex shapes, steel, devices with complex shapes, devices with hinged or mated surfaces or devices with hinged or mated surfaces or devices with lumens be addressed?devices with lumens be addressed?
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Questions for the Advisory Questions for the Advisory PanelPanel
5.5. How closely should the experimental How closely should the experimental treatment conditions for a product/process treatment conditions for a product/process indicating to reduce TSE infectivity indicating to reduce TSE infectivity replicate the actual conditions under which replicate the actual conditions under which the proposed product/process would the proposed product/process would actually be used?actually be used?
Should such issues as instrument cleaning, Should such issues as instrument cleaning, conditions which might fix protein to conditions which might fix protein to instruments, possible interactions between instruments, possible interactions between the new product/process and standard the new product/process and standard cleaning agents, sterilizer cycles used, cleaning agents, sterilizer cycles used, etc., be considered?etc., be considered?
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Questions for the Advisory Questions for the Advisory PanelPanel
6.6. Considering the current state of the Considering the current state of the science and existing investigative science and existing investigative methods for estimating the methods for estimating the potential for TSE transmission, can potential for TSE transmission, can an indication for use of “complete an indication for use of “complete elimination of TSE infectivity” be elimination of TSE infectivity” be validated?validated?
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