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
TABLE OF CONTENTS
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.
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?
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