MEDICAL DEVICES ADVISORY COMMITTEE MEETING OF THE GENERAL HOSPITAL AND PERSONAL USE DEVICES PANEL Transmissible Spongiform Encephalopathy (TSE) September

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


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.



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.


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.



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”.



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



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



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.



Presentations by FDAPresentations by FDA


Elaine S. Mayhall, PhDElaine S. Mayhall, PhD

Estelle Russek-Cohen, PhDEstelle Russek-Cohen, PhD

Ronald BrownRonald Brown



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




IntroductionIntroduction

Elaine Schalk Mayhall, Ph.D.Elaine Schalk Mayhall, Ph.D.

Infection Control Devices BranchInfection Control Devices Branch


Center for Devices and Radiological HealthCenter for Devices and Radiological Health



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.


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


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


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


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



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



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


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


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


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


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)


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



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.



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



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.




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




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




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




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



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.


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


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


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?



In-Vivo Models of TSE In-Vivo Models of TSE TransmissionTransmission

Experimental Design IssuesExperimental Design Issues


Branch ChiefBranch ChiefInfection Control Devices BranchInfection Control Devices Branch


Center for Devices and Radiologic HealthCenter for Devices and Radiologic Health


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



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


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



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?



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



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



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


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






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



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?



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



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.


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



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?



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?



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.)



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?



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



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”



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



““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”



““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



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?




Is the experimental differenceIs the experimental difference

Statistically Significant?Statistically Significant?

Clinically Significant?Clinically Significant?




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.



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?


Products/Processes which Products/Processes which Reduce TSE TransmissionReduce TSE Transmission

Risk / Benefit RatioRisk / Benefit Ratio



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



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



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



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



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?


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


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


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)


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


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


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.


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?


““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


A Cage Battery A Cage Battery


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


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


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)


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


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


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?


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


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


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


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


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


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


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.


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


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


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.


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%)


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%


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


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.


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


Iatrogenic CJD Risk from Iatrogenic CJD Risk from Reprocessed Neurosurgical Reprocessed Neurosurgical


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


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.


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


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)


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?


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).


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)


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)


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


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)


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


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


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


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


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


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.


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


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


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


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


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


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


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


Probabilistic ModelProbabilistic ModelDistribution typesDistribution types


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


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


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.



_______________PANEL QUESTIONS_______________


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.



2.2. Discuss the relevance of various Discuss the relevance of various design features of such validation design features of such validation studies.studies.



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?



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?



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?



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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