October 31, 2005HHS/FDA/CDRH1. October 31, 2005HHS/FDA/CDRH2 Scientific Issues in Evaluating...

October 31, 2005October 31, 2005 HHS/FDA/CDRHHHS/FDA/CDRH 11


Scientific Issues in Evaluating Scientific Issues in Evaluating Products Intended to Products Intended to

Decontaminate Surgical Decontaminate Surgical instruments Exposed to TSE instruments Exposed to TSE

Agents Agents Discussions of a Recent FDA Discussions of a Recent FDA

Device Advisory PanelDevice Advisory Panel

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

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


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.



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


Transmissible Spongiform Transmissible Spongiform EncephalopathyEncephalopathy

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


Iatrogenic Transmission of Iatrogenic Transmission of Creutzfeldt-Jakob diseaseCreutzfeldt-Jakob disease

Source #Source # Incubation Incubation periodperiod

Neurosurgery 4Neurosurgery 4 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


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


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.


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


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


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



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


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)


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


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


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

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


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.


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


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.



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


MHRA CommentsMHRA Comments

New deactivation agents are being New deactivation agents are being presented to the market where the presented to the market where the models chosen may not be models chosen may not be substantive enough to ensure the substantive enough to ensure the product/process is fully validated.product/process is fully validated.


MHRA SummaryMHRA Summary

Understanding of prions and their adherence Understanding of prions and their adherence onto surgical instruments is advancing at a onto surgical instruments is advancing at a rapid pace, but what about other materials rapid pace, but what about other materials used in the manufacture of surgical used in the manufacture of surgical instruments (eg titanium, plastics)instruments (eg titanium, plastics)

There does not appear to be agreement There does not appear to be agreement within the scientific community on the most within the scientific community on the most appropriate animal/prion strain model that is appropriate animal/prion strain model that is representative of the human form of vCJD for representative of the human form of vCJD for use in research and product/process use in research and product/process developmentdevelopment


_______________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.


Answers from the Advisory Answers from the Advisory PanelPanel

1. The Advisory Panel agreed that yes, 1. The Advisory Panel agreed that yes, it is reasonable that a it is reasonable that a product claim for “Reducing TSE product claim for “Reducing TSE Infectivity” on stainless steel Infectivity” on stainless steel instruments be validated using instruments be validated using animal studies of TSE transmission.animal studies of TSE transmission.



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



2. The Advisory Panel agreed that the following 2. The Advisory Panel agreed that the following were relevant to validation studies for a were relevant to validation studies for a claim of TSE reduction:claim of TSE reduction:

Maximal study durationMaximal study duration Study population large enough for “sufficient Study population large enough for “sufficient

statistical validity”statistical validity” Log reduction in infectivity should be as large Log reduction in infectivity should be as large

as possibleas possible



2. Relevant validation study features-cont.2. Relevant validation study features-cont.

Human prion sources should be studied – Human prion sources should be studied – both sporadic and variant CJDboth sporadic and variant CJD

Transgenic mouse models are appropriateTransgenic mouse models are appropriate New clinical human CJD sources may be New clinical human CJD sources may be

characterized against known animal TSE characterized against known animal TSE models and/or the WHO reference strainsmodels and/or the WHO reference strains



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?


Answers from the Advisory Answers from the Advisory panelpanel

3. The Advisory panel agreed that “log 3. The Advisory panel agreed that “log reduction in infectivity” is the appropriate reduction in infectivity” is the appropriate study endpoint for validation of “reducing TSE study endpoint for validation of “reducing TSE infectivity” claims.infectivity” claims.

The Advisory Panel did not specify a particular The Advisory Panel did not specify a particular level of reduction level of reduction

The Advisory Panel stated that linking the The Advisory Panel stated that linking the mean incubation time to log reduction in mean incubation time to log reduction in infectivity could demonstrate clinical infectivity could demonstrate clinical relevancerelevance



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?



4. Additional study issues which FDA 4. Additional study issues which FDA should consider for claims for devices should consider for claims for devices other than “simple” steel instrumentsother than “simple” steel instruments

modification of the test wire surface to modification of the test wire surface to better mimic clinical conditionsbetter mimic clinical conditions

testing different materialstesting different materials testing simulated/surrogate device testing simulated/surrogate device

shapes shapes



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?



5. The panel agreed that yes, they 5. The panel agreed that yes, they wished to see the study conditions wished to see the study conditions simulate the clinical conditions of simulate the clinical conditions of instrument processing as closely as instrument processing as closely as possible. The Panel specifically possible. The Panel specifically mentioned attention to the challenge mentioned attention to the challenge of a large bioburden, dried on an of a large bioburden, dried on an instrument before processing.instrument before processing.



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?



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

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