U.S.
Department of Health and Human Services
Food and Drug Administration
Center for
Devices and Radiological Health
CENTER FOR DEVICES AND RADIOLOGICAL
HEALTH MEDICAL DEVICES ADVISORY COMMITTEE
MEETING OF THE
GENERAL HOSPITAL AND PERSONAL USE
DEVICES PANEL
Tuesday, September 27, 2005
Hilton Washington DC North
Ballroom
Gaithersburg, Maryland
TABLE OF CONTENTS
I. EXECUTIVE SUMMARY
This Advisory Panel is asked
to address the issues surrounding the evaluation of products and/or processes
intended to reduce the bioburden of the Creutzfeldt-Jakob disease transmissible
agent on contaminated surgical instruments. The Division of Anesthesiology,
General Hospital, Infection Control and Dental Devices (DAGID) has not yet
approved for marketing any products intended for this use. However, the
Division believes that there is interest in the development of such products.
The scientific literature contains several recent publications describing
preliminary studies on compounds which seem to have some effectiveness in
reducing the ability of inoculates to transmit disease in animal models of
transmissible spongiform encephalopathy (TSE). The Division wishes to prepare
for the evaluation of such products, if submitted, by seeking guidance from the
Panel. DAGID has reviewed the relevant
scientific literature and has considered relevant issues in collaboration with
the Office of Biometrics and Surveillance and the Office of Science and
Engineering Laboratories of the Center for Devices and Radiologic Health
(CDRH).
The transmissible spongiform
encephalopathies (TSE), named for their characteristic neuropathologic changes
are fatal neurodegenerative diseases of animals and of man. Scrapie, a disease
of sheep, was first described in the 18th century. In 1954,
Sigurdsson suggested that this was a chronic encephalitis caused by a
transmissible agent with a long incubation period. When kuru was described in
the Fore peoples of New Guinea in the 1950s, the similarity of the
neuropathology to scrapie was recognized even as an epidemiologic connection
was observed between kuru and the ritual consumption of organs and tissues of
the deceased at funeral feasts. Kuru was most common in women and children,
those most likely to consume brain tissue; their mean incubation period was
shorter than for those who consumed other tissues. Once the practice of ritual
cannibalism was stopped, the incidence of kuru dropped. No one born since this
practice ended has developed kuru. Animal models were used to demonstrate that
inoculation of brain tissue from patients with kuru and from animals with
scrapie could transmit these diseases. Transmissibility was also shown for
Creutzfeldt-Jakob disease (CJD), a neurodegenerative disease of man first
described in the 1920s.
In the past 50 years, the
work of many investigators, using animal models of TSE, has revealed much about
the pathogenesis, transmissibility, molecular biology, genetic susceptibility
and epidemiology of these diseases. The nature of the infectious agents causing
TSE has been a source of controversy. The term “prion” was coined by Dr.
Stanley Prusiner in 1982 to indicate that these transmissible agents were
“proteinaceous infectious particles” lacking nucleic acids. Purification of
material from infected brains identified the “prion protein” PrP which is the
major, if not exclusive, component of prions. The gene PRNP produces PrPc (cellular
PrP), the normal isoform of PrP. It is also called PrPsen (sensitive
to proteinase). Prpc is a monomer. It is sensitive to
proteinase K and to detergents and is attached to the cell surface. It has
rapid synthesis and degradation rates. Levels of PrPc are highest in
the central nervous system (CNS) and are higher in neurons than in glial cells.
It is also found in extraneural tissues. The scrapie isoform of PrP, PrPsc,
is organized into oligomers and polymers, is resistant to proteinase K and to
detergents and is found predominately in vesicles. It is also called PrPres.
Its synthesis and degradation rates
are much slower than those of the normal isomer. The term PrPres
denotes all abnormal isoforms of PrPc (resistant to proteinase K).
It is the abnormal isoform of PrPc (PrPsc or PrPres)
which accumulates in the CNS in Creutzfeldt-Jakob disease. The presence of mutations in the PRNP gene can also
induce conversion of the normal isoform PrPc to the abnormal isoform
PrPsc (PrPres), resulting in familial Creutzfeldt-Jakob
disease, fatal familial insomnia or Gerstmann-Straussler-Scheinker syndrome. At
least 30 mutations in PRNP have now been described leading to these genetically
determined disease phenotypes. Inoculation of brain from these patients
into animals will transmit these
abnormal protein isoforms (prions) and cause disease and death.
Most cases of
Creutzfeldt-Jakob disease (>85%) are “sporadic” with no obvious source.
Familial CJD and related genetically determined diseases cause 5% to 15% of
human TSE disease. Rare iatrogenic cases of CJD due to transfer of infected CNS
material between patients have also been described. Most iatrogenic CJD has
been caused by the administration of human pituitary growth hormone (143 cases),
human pituitary gonadotropin (4 cases), use of human dura mater in surgical
procedures (114 cases), corneal transplantation from infected patients (3
cases), and use of contaminated neurosurgical instruments (5 cases) and
stereotactic depth EEG electrodes (2 cases) which had been previously used on
patients with CJD.
All of the 7 reported
instances of CJD transmission by contaminated neurosurgical instruments (5
cases) or depth EEG electrodes (2 cases) occurred between the 1950s and the
1970s. Details of the cleaning/sterilization procedures used were published
only for the stereotactic EEG electrodes. These were sterilized in formaldehyde
vapor, a process later shown to be ineffective in reducing TSE
transmissibility. Although the published information on these cases is limited,
the reported time sequences suggest that other patients were also exposed to
these contaminated items. Nevertheless, these are the only reported cases of
CJD due to intraoperative contamination. Intraoperative transmission of CJD has
not been reported in the last 25 years. There have also been several reports of
the reuse of CJD-contaminated instruments before the diagnosis was confirmed on
the initial patient and before the instruments were removed from use. No cases
of CJD resulting from these exposures have yet been reported although the
prolonged latency period between exposure and the development of clinical
disease suggests that some patients may eventually develop CJD. Epidemiologic
studies have attempted to determine whether prior surgery is a risk factor for
the development of Creutzfeldt-Jakob disease. These studies have been small,
with potential problems in the choice of control populations. The estimated
risk for CJD associated with general surgery or with neurosurgical procedures
has varied by study. A statistically significant association between CJD and
prior surgery has not been consistently shown. Isolated reports of CJD in
healthcare workers with likely or potential occupational exposure to CJD have
been published; however, the incidence of CJD in healthcare workers does not
appear to exceed the incidence of CJD in the general population.
Interest in the pathogenesis
and transmission potential of sporadic Creutzfeldt-Jakob disease has been
heightened by the appearance of an epidemic of bovine spongiform encephalopathy
(“mad cow disease”) in the UK which has now resulted in cross-species
transmission to man, causing “variant CJD”. The BSE epidemic spread among
cattle in the United Kingdom (UK) through the ingestion of animal feed
containing neural tissue from scrapie-infected sheep and infected cattle. Very
large numbers of people have consumed meat from infected cattle, some of which
may have been contaminated by neural tissue and are therefore at risk for the
development of variant CJD (vCJD). Surveillance for variant CJD has identified
141 cases since 1994. Although the number of cases of variant CJD reported
annually is now declining, CJD can have a very long incubation period. It is
possible that the incidence of vCJD may increase again in future years. There
is concern about the risk of surgery-related transmission of CJD in populations
in which the prevalence of presymptomatic vCJD may be increasing. BSE appears
to be more likely than other TSE to cross the “species barrier”. The relatively
new agents causing feline spongiform encephalopathy and exotic ungulate
spongiform encephalopathy appear to be very closely related to BSE and probably
spread into these new host species by consumption of BSE-contaminated animal
feed.
Studies at the National
Institutes of Health (NIH) in the 1980s examined various
sterilization/disinfection methods for their ability to reduce the transmission
of TSE in animal models of disease. These results from these studies formed the
basis for recommendations by various authorities for procedures to be used when
handling instruments potentially or definitely contaminated by CJD. These
recommendations have never been evaluated in clinical trials both for ethical
reasons and because of the rarity of CJD patients. The current draft CDC
guidelines for handling instruments known to be or possibly contaminated by CJD
incorporate a risk analysis. Not all tissues have an equal likelihood of
transmitting CJD. CNS tissue is clearly the most risky source. Excellent
cleaning to reduce the bioburden on instruments is essential. Recommended
procedures are based upon experimental data showing reduction in TSE
transmissibility. Recommendations for surgical instruments include steam
sterilization either in a prevacuum sterilizer at 1340 C for 18
minutes or in a gravity displacement sterilizer at 1210 C to 1320
C for one hour. Immersion of the instruments in 1 N NaOH for one hour
is another recommended procedure. These
procedures are corrosive (NaOH) or unsuitable for heat-sensitive instruments.
Processed instruments must be recleaned and then sterilized/disinfected again
by “usual” methods after the initial treatment to reduce TSE infectivity.
Obviously, more convenient and less damaging treatment options for contaminated
instruments would be desirable. However, any such treatments/processes would
also need to be effective.
Demonstration of TSE
transmission from one individual to another and demonstration that transmission
of TSE between individuals can be reduced presently requires the use of a live
animal model. Clinical immunologic assays which demonstrate the presence of PrPsc
in tissue are sensitive and specific and useful in patient diagnosis.
They were not been designed for use on instruments and their interpretation
addresses the presence or absence of PrPsc but not its
“transmissibility”. Tissue cultures have been used to a degree in studies of
TSE biology, but there are, as yet, no studies correlating “transmissibility”
between hosts with results in tissue culture.
In animal studies, TSE
transmission must overcome the “species barrier”. Efficient transmission of PrPsc
native to one species to a different host may require a large infecting
inoculum and may have a longer incubation time to symptomatic illness. Serial
passage of a TSE strain in a new host may result in “adaptation” to the new
host. Prolonged laboratory passage of a TSE strain may also result in the
development of differences in the strains when compared to the original source
isolate. A prion strain which has “adapted” to a host may now replicate more
easily and produce a higher tissue burden of prions than seen originally. Genetic manipulation of the host may
facilitate TSE infection. Transgenic mouse strains expressing human PrPc can
be more easily infected with human CJD. Over the years, investigators have used
a variety of TSE sources and several animal host species for the study of TSE,
including genetically altered hosts.
The hosts studied in models
of TSE transmissibility are usually small mammals –hamsters, guinea pigs, mice.
These are easier and less expensive to house and to manipulate. Their
relatively short life spans (about 2 years) make it feasible to study these
animals throughout their normal lifespan. It is feasible to use many animals in
a study. Transfer of TSE can be performed in several ways; most often,
infectious material is inoculated directly into the CNS. The TSE source is
brain tissue from an infected animal. It is usually diluted for ease in
handling. It may have been previously frozen. Inoculum may come from a single
brain or from a pool of brains. A source may be used on one occasion or over a
period of time. The method of inoculation of the CNS may be injection by needle
or insertion of an inoculum-coated wire. The wire may be left in place or
withdrawn.
Once the CNS inoculum has
been administered to the host animals, they are observed for the development of
the symptoms of TSE disease and then sacrificed for examination. Animals who
have received inoculum pre-treated to reduce the transmission of TSE and who
remain asymptomatic may be observed until close to the end of their normal life
span and then sacrificed for examination at a predetermined endpoint. The
presence of TSE infection on neuropathologic examination of asymptomatic
animals sacrificed at a predetermined endpoint has been reported (Jackson G,
McKintosh E, Fleshig E et al. “An
enzyme-detergent method for effective prion decontamination of surgical steel” J Gen Virol 2005 86:869-878).
The endpoints of studies of
TSE transmissibility in animal models include “log reduction in infectivity”,
incubation time interval and improvement in median survival or percent survival
beyond a given time. To “measure” these endpoints, results in the experimental
groups must be compared with the results obtained for a group of control
animals each of which receives one dose in a series of progressively diluted
doses of the test inoculum. The infectious dose in experimental animals,
expressed as per gram of brain tissue, will be estimated by determining how the
animals exposed to the control inoculum in question fare. The incubation time
to symptoms is expected to increase as the infectious dose decreases. As the
infectious dose falls, some and eventually all of the animals will survive
without infection. Results in the experimental group will be measured by
comparison to the control group. The quantitation of these results is,
therefore, relative. Measurement of the “log reduction in infectivity”, the incubation
time interval, the median survival time and the percent survival all require
comparison to results in the control animals. The “log reduction in
infectivity” is the estimated difference between the infectivity of the
inoculum placed into the CNS before and after the treatment under
investigation. This difference (assuming that the treatment being investigated
is effective) will result in changes in the median survival and percent
survival between the control and treatment groups. It is very difficult to
measure/estimate the amount of “starting” inoculum coated on a wire. Although
the term “log reduction in infectivity” seems to imply direct measurement of
the infectious dose, this is not the case.
The degree of statistical
confidence in the results of studies of TSE infectivity will be affected by the
number of animals used to measure each data point. As an example, if 4 animals
receive a very small (very dilute) dose of infectious inoculum and all of the 4
animals survive without disease, we may conclude that this dose will not
reliably infect 100% of a population. It cannot be concluded, however, that
this dose would never infect any animals in a larger population. If the
population of animals receiving this dose were larger, what is the likelihood that
all would survive? Might the survival rate actually be closer to 50% or to 90%?
Many of the published studies
on reducing the transmissibility of TSE have reported results on 4 to 12
animals per treatment examined. There are many factors which can influence the
results of studies in animals. Study protocols should be designed to minimize
or to randomly distribute these ‘sources of variability” in order to improve
the accuracy of the study results. “Sources of variability” include the TSE
inoculum – one brain or several, inoculation on one day or several, inoculation
of the members of one test group all at one time or at more than one time.
Housing is also a source of variability – are members of the same group always
housed in one cage or distributed among several cages? Are the cages of one
group always on the same cage rack, same shelf and same room location or is
housing randomly distributed? Are animals which die prematurely for reasons
other than TSE accounted for in the statistical analysis and in the study size?
Are their brains examined after death?
When a compound or a process
is evaluated in an animal model of TSE transmissibility, the question of how
well the model represents the real “in-use” situation in healthcare must be
considered. A “used instrument” will be contaminated by blood and tissue. This
instrument will then be “cleaned”. Estimates for the efficiency of soil removal
by cleaning are approximate and are often based on quantitative bacterial
cultures. Certain instrument features are particularly difficult to clean –
hinges, mated surfaces and lumens. Many TSE investigators are now using small
(5 mm) stainless steel wires coated
with inoculum in their studies of TSE transmissibility. The material is a
suitable stand-in for many instruments. The simple shape, however, and the
previously “unused” surface do not closely replicate actual surgical
instruments.
Applying a compound or a
treatment process to a 5mm wire in the laboratory may not adequately reflect
the conditions in which an actual instrument is cleaned and then sterilized in
a hospital. Instrument cleaning is often initially performed in an ultrasonic
washer using detergents and perhaps other agents as well. Inspection for any
remaining soil follows (with repeat cleaning if needed). Surgical instruments
are usually wrapped or packaged before sterilization so that they can be stored
“sterile” until needed again. TSE experimental protocols coat the wires with
inoculum, dry them, “treat” them and then inoculate them into the test animal.
These experimental “treatment” conditions are not always designed to replicate
procedures in a hospital Sterile Processing Department.
What is the magnitude of the
risk of CJD transmission by contaminated instruments in the United States at
the present time? The estimated annual incidence of Creutzfeldt-Jakob disease
in the United States at present is 1 case per 1 million people per year.
Ongoing surveillance by CDC has not detected any increase in this rate over
many years. Precautions were implemented some years ago to reduce the
likelihood of BSE transmission in the United States and to perform active
surveillance for BSE in cattle and for variant CJD in humans. Only two
BSE-infected cows have been identified in the US so far; both were born in Canada
and did not enter the food supply. To date, only one patient has developed vCJD
in the US; this patient had lived in the UK for many years and moved to the US
shortly before becoming ill. A risk assessment for Creutzfeldt-Jakob disease
transmission by contaminated instruments in the US has been performed by OSEL and will be presented to the Panel.
The risk assessment is modeled on one performed in the UK to evaluate the risk
that surgical instruments in the UK might transmit vCJD. The OSEL risk assessment
uses the current epidemiologic status of sporadic CJD incidence in the US for
its calculations. No cases of iatrogenic CJD transmission by contaminated
instruments have ever been reported from the US. The risk that contaminated
instruments will transmit CJD here is considered to be very small at present.
This OSEL risk assessment will not address any risk from vCJD in the US.
The Food and Drug
Administration (FDA) needs to consider whether the introduction of
products/treatments shown to reduce the transmission of TSE by contaminated
instruments would change current clinical practice or would affect patient
safety. One concern would be the development of a false sense of security among
healthcare workers. There might be less attention paid to the prompt
identification of patients with possible CJD and to the need to immediately
quarantine any surgical instruments used in the care of such a patient as
currently recommended by CDC. The actual cleaning of contaminated instruments
might be less meticulous if healthcare workers believed that a TSE
transmission-reducing product would actually remove all risk of TSE
transmission. A “difficult to clean” contaminated instrument might not be
discarded as it would have been prior to the availability of a product to
reduce TSE transmissibility. The actual use of a product/process to reduce TSE
transmission might increase the time and the effort needed to process surgical
instruments.
Should the introduction of
products/treatments shown to reduce the transmission of TSE change current
clinical practice? The current endpoints used to demonstrate effectiveness in
studies of TSE transmission measure changes in transmission of infectivity only
by approximation. They can indicate the magnitude of the change in the model
system studied but do not directly correlate with clinical events. The lower
limit of detection in these models is unknown. Complete removal of TSE
infectivity cannot currently be determined. Therefore, if FDA should, in
future, approve a product/process for a labeling claim of reducing TSE
infectivity, this should not be interpreted to mean that current CDC guidelines
for handling of materials contaminated by TSE no longer need to be
followed. Any changes to the guidelines
would be decided by that Agency. At present, if FDA were to approve any
products for marketing with a claim of reducing TSE transmission, these
products would be only adjuncts to current procedures as recommended by
CDC.
II.
DRAFT PANEL
QUESTIONS
Q1. Assuming
that a product sponsor seeks a claim for “reducing TSE infectivity” on
stainless steel instruments, is it reasonable for such a claim to be validated
using animal studies of TSE transmission?
Q2. Discuss
the relevance of various design features of validation studies.
Q3. Of the
three study endpoints cited in the literature – log reduction in infectivity,
mean incubation time and survival curve, which, if any, of these endpoints may
be adequate for the validation of a “reducing TSE infectivity” claim? How may
clinical benefit be estimated from these endpoints?
Q4. What
additional issues should be considered by FDA when evaluating claims for devices
other than simple stainless steel surgical instruments? How can devices constructed from or
including materials other than stainless steel, devices with complex shapes,
devices with hinged or mated surfaces or devices with lumens be addressed?
Q5. How
closely should the experimental treatment conditions for a product/process
claiming to reduce TSE infectivity replicate the actual conditions under which
the proposed product/process would actually be used? Should such issues as
instrument cleaning, conditions which might fix protein to instruments,
possible interactions between the new product/process and standard cleaning
agents, sterilizer cycles used, etc., be considered?
Q6.
Considering the current state of the science and existing investigative methods
for estimating the potential for TSE transmission, can a claim of “complete
elimination of TSE infectivity” be validated?
III.
PANEL TOPIC
REFERENCES
General Background
1. Collins
SJ, Lawson VA, Masters CL
Transmissible spongiform encephalopathies
Lancet 2004; 363:51-61
2. Beisel C,
Morens D Variant Creutzfeldt-Jakob
disease and the acquired and
transmissible spongiform
encephalopathies CID 2004;
38:697-704
3. Prusiner,
SB Shattuck Lecture – Neurodegenerative
diseases and prions
N Engl J Med 2001; 344:1516-1526
4. Collinge,
J Variant Creutzfeldt-Jakob
disease Lancet 1999;
354:317-323
5. Harris,
D Cellular biology of prions Clin Micro Rev 1999; 12:429-444
6. Will RG,
Ironside JW, Zeidler M et al. A new
variant of Creutzfeldt-Jakob
disease in the UK Lancet 1996; 347:921-925
Surveillance for Creutzfeldt-Jakob Disease
7. Centers
for Disease Control Surveillance for
Creutzfeldt-Jakob disease-United States Morb Mortal Wkly Rep 1996;
45(31):665-668
8. Centers
for Disease Control Creutzfeldt-Jakob
disease in the United States, 1979-1994;
using national mortality data to assess the possible occurrence of variant cases
Emerging Infect Dis 1996; 2:333-337
9. Brown P,
Gibbs Jr. CJ, Rodgers-Johnson P et al.
Human spongiform encephalopathy: the National
Institutes of Health series of 300 cases of experimentally
transmitted disease Ann
Neurol 1994; 35:513-529
Iatrogenic Creutzfeldt-Jakob Disease
10. Brown P,
Preece M, Brandel J-P et al.
Iatrogenic Creutzfeldt-Jakob disease at the
millennium Neurology 2000;
55:1075-1081
11. Bernoulli
C, Siegfreid J, Baumgartner G et al.
Danger of accidental person-to
person transmission of Creutzfeldt-Jakob
disease by surgery Lancet 1977;
1:478-479
12. Foncin JF,
Gaches J, Cathala F at al.
Transmission iatrogene interhumaine
possible
de maladie de Creutzfeldt-Jakob avec atteinte des grains du cervelet
Rev
Neurol (Paris) 1980; 136:280 “REQ 13499259”
13. Will RG,
Matthews WB Evidence for
case-to-case transmission of Creutzfeldt-
Jakob
disease J Neurol, Neurosurg and
Psychiatry 1982; 45:235-238
“ REQ
13499261”
Recommendations for the Processing of CJD-Contaminated
Instruments
14. McDonnell
G, Burke P The challenge of prion
decontamination CID 2003; 36:1152-1154
15. Weber DJ,
Rutala WA Creutzfeldt-Jakob disease:
prevention of nosocomial acquisition Seminars
in Infection Control 2002; 2:51-63
16. Rutala WA,
Weber DJ Creutzfeldt-Jakob disease:
recommendations for
disinfection and sterilization CID
2001; 32:1348-1356
17. Brown SA,
Merritt K, Woods TO et al. Effects
on instruments of the World
Health Organization-recommended protocols for
decontamination after
possible exposure to transmissible spongiform
encephalopathy-contaminated
tissue J Biomed Mater Res Part B
Appl Biomater 2005; 72B:186-190
Experimental Studies of Laboratory Transmission of TSE
18. Weissman
C, Enari M, Klohn P-C et al.
Transmission of prions JID
2002; 186(Suppl
2):S157-165
19. Jackson
GS, McKintosh E, Flechsig E et al.
An enzyme-detergent method for
effective prion decontamination of surgical
steel J Gen Virol 2005; 86:869-878
20. Brown P,
Rohwer R, Green EM et al. Effect of
chemicals, heat and histopathologic processing on
high-infectivity hamster-adapted scrapie virus JID 1982; 145:683-687
21. Brown P,
Gibbs Jr CJ, Amyx HL et al. Chemical
disinfection of Creutzfeldt-
Jakob
virus N Engl J Med 1982;
306:1279-1282
22. Brown P,
Rohwer R, Gajdusek DC Newer data on
the inactivation of scrapie virus
or Creutzfeldt-Jakob virus in brain tissue
JID 1986; 153:1145-1148