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U.S. Department of Health and Human Services

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FY 2001 Reuse / Sterilization / Disinfection / Infectious Disease Diagnostics

FDA has traditionally not regulated reprocessing of single-use devices, but recently decided that regulation was necessary to assure the safety and efficacy of reprocessed medical devices. The OST Reuse Program is designed to address the issues of safety and efficacy associated with the reuse of devices that are intended as single-use devices (SUDs). Data and other information obtained in this OST research program have contributed to this policy and will help in the final formulation and implementation of regulations. The experience gained from this program will allow CDRH to understand the problems and ask the right questions related to SUD reprocessing. SUDs were intended by the original equipment manufacturer (OEM) to be discarded after single use and not to be reused on another patient. SUDs used in interventional cardiology and in gastrointestinal procedures are obtained from Walter Reed Army Hospital and the Washington Hospital Center. Difficulties in cleaning these devices indicated unique problems with access to lumens and interstices that may contain blood and tissue. If the device cannot be cleaned, it cannot be reprocessed safely. Consequently, a potential hazard may exist if the device is reused on another patient. These lumens and interstices are narrow and opaque, and protocols to clean and validate cleaning are being developed. Cleaning and sterilization are safety issues. SUDs were also examined for performance (efficacy) and damage associated with use and cleaning. Because of concerns for laboratory personnel safety, the retrieved devices must be disinfected and cleaned prior to being handled and inspected. Some devices were examined after simulated reuse and reprocessing. A large collection of devices and models of these devices are available for further study. Interventional cardiology devices include many models of percutaneous transluminal coronary angioplasty catheters (PTCA) [balloon catheters], balloon inflators, electrophysiology catheters, various cardiac ablators, ultrasonic imaging catheters, angiography catheters, guiding catheters, revascularization catheters, and balloon catheters for wedge procedures. The gastrointestinal devices include various models of GI biopsy forceps and snares, devices for retrieving gallstones (balloons, snares, ERCP devices), and various GI catheters. Ensuring clean SUDs is complex as each device has its own specific cleaning needs.

Protocols for cleaning, sterilizing and evaluating performance of these devices are being developed in OST. These studies provide independent data to support review and regulatory decision-making related to the adequacy of reprocessing procedures for SUDs. This research is designed to uncover problems that a reprocessor firm may inadvertently confront while reprocessing SUDs and that CDRH needs to be aware of in regulating the practice of reprocessing SUDs. The use of simple techniques, reagents, and readily available equipment is emphasized so that the results are transferred to the actual reprocessing undertaken in hospitals and third party reprocessors. However, newer technologies are also being incorporated to understand important advancements that must be considered for managing risks in the future.

This OST research program has contributed independent data and information that is being used in compliance actions and in device approvals. The output from this research has already played a major role in formulating the CDRH policy for third party reprocessors and hospitals. All third party reprocessors had to submit PMA applications for reprocessing Class III devices by February 14, 2001, and submit 510K applications for other devices by August 14, 2001. Hospitals were to submit PMA or 510K applications by August 14. The OST research team is active in reviewing these documents and in developing standards for cleaning methods/validation and issues of sterilization. Most recent, the research team has provided training programs to communicate and share knowledge of the critical reuse issues so as to improve and enhance performance of ORA field inspectors.

CDRH continues to be actively involved with the regulatory evaluation of premarket applications for commercial in vitro diagnostic devices. A relatively recent and important component of this effort is the evaluation of premarket nucleic acid-based kits used to detect and identify infectious microorganisms. OST scientists in collaboration with ORA/WEAC participated in the International Laboratory Study on Chemical Disinfectants. This includes over 20 laboratories around the world in a round-robin (Ring Test) study to validate methods for disinfecting medical devices. The OST/ORA labs are the only United States participants. OST scientists perform laboratory research projects that involve utilizing equipment and methodologies associated with these devices, and this experience enables them to 1) participate effectively in the CDRH regulatory review of the devices, 2) make informed regulatory decisions concerning the safety and efficacy of the devices and procedures, and 3) efficiently standardize the associated methodology.  

Peptide Nucleic Acid Probe Detection of Mutations in Mycobacterium tuberculosis Genes Associated with Drug Resistance

Key words: Mycobacterium tuberculosis, diagnostics, polymerase chain reaction, peptide nucleic acid, antibiotic, drug resistance.

Pulmonary tuberculosis is one of the most important, life-threatening bacterial diseases in the world. In recent years tuberculosis control efforts have been severely threatened by the emergence of potentially dangerous drug resistant strains of Mycobacterium tuberculosis (MTB). Many of the specific gene mutations that cause drug resistance in MTB are point mutations in known chromosomal genes. In vitro diagnostic devices that utilize new technology for the rapid detection of drug-resistant MTB strains are needed, since classical bacteriological methods are tedious and time consuming. OST scientists and collaborators from CBER are developing a PCR-peptide nucleic acid (PNA)-based ELISA as a diagnostic method for the rapid detection and identification of point mutations in genes associated with isoniazid and rifampin resistance in MTB. PNA probes are the basis for a new technology for detecting mutant nucleic acids, including single-point mutations because they have high thermal stability, strong binding capacity, and high binding specificity.

Specific-point, mutation-containing sequences and wild-type sequences of cloned mycobacterial genes were PCR amplified, denatured, and hybridized with PNA probes bound to microplate wells. Using 15-base PNA probes, the experimental conditions suitable for detecting clinically relevant point mutations in the two MTB genes were established. Hybridization of PCR-amplified sequences that contained these point mutations with complementary mutation-specific PNAs resulted in significant increases in ELISA response compared to hybridization using wild type-specific PNAs. Conversely, PCR-amplified wild-type sequences hybridized much more efficiently with wild-type PNAs than with the mutation-specific PNAs. Using the MTB-cloned genes and PCR-PNA-ELISA format developed here, MTB sequences containing point mutations associated with drug resistance could be identified in less than 24 hours. The results of this research have been published in the journal BioTechniques. The laboratory experience gained from the project also enabled the investigators to make informed pre-market evaluations of commercial in vitro diagnostic devices used for detecting infectious microorganisms and to participate in developing molecular diagnostics-related biotechnology standards.

Microarray-Based In vitro Diagnostic Devices: Detection and Identification of Antibiotic Drug Resistant Strains of Mycobacterium tuberculosis

Key words: microarray, diagnostics, Mycobacterium tuberculosis, antibiotic, drug resistance.

Public health is threatened by the emergence of potentially deadly antibiotic-resistant mutant strains of M. tuberculosis. To facilitate diagnosis and appropriate treatment, faster and higher-throughput in vitro diagnostic devices are needed to detect mutations associated with M. tuberculosis drug resistance. The purpose of this OSCC-funded project is to evaluate the use of state-of-the-art microarray technology for the rapid and accurate detection and identification of numerous drug resistant strains of M. tuberculosis. OST scientists in collaboration with CBER, NCTR, and ORA investigators are studying device performance (e.g., analytical sensitivity, specificity, and repeatability), with a goal of standardizing the methodology. The knowledge and experience gained in this project will be used in regulatory evaluation of premarket microarray-based in vitro diagnostic device applications submitted to the Center.

Product Safety/Disease Control and Prevention

Key words: Transmissible Spongiform Encephalopathies (TSEs), product safety, infection control, TSE risks

An OST scientist served as Chair of the CDRH TSE Working Group and as a key member of the FDA TSE Coordinating Committee. OST scientists are providing leadership and scientific expertise in Center/Agency programs to resolve numerous cross-cutting scientific and regulatory issues regarding TSEs that impact FDA-regulated products with broad implications for public health.

TSEs are chronic, degenerative, and uniformly fatal neurological disorders of animals and humans. Two of the human TSE diseases are classical Creutzfekit-Jakob Disease (CJD) and a new variant of CJD called vCJD. For CDRH, emphasis is on preventing human TSE transmission through medical devices containing or manufactured with bovine-derived materials, human tissue-based devices, use and reuse of surgical instruments, and assisting device manufacturers in developing diagnostic tests for these diseases.

Significant accomplishments in support of Center /Agency TSE initiative include the following:

  • Established approaches to address CDRH-specific items in the FDA TSE Action Plan through deliberations of the CDRH TSE Working Group and appropriate Center staff;
  • Developed the FDA "Proposed BSE Rule" which would make bovine and bovine materials from BSE-positive or BSE high-risk countries prohibited materials in the manufacture of FDA-regulated products;
  • Developed a draft plan to maintain an updated database of products containing or manufactured using animal derived materials;
  • Developed the BSE Contingency Plan, which outlines measures to be taken in the event of a potential case of BSE in the U.S. and participation in ORA satellite broadcast as outreach/education to the field and constituent communities;
  • Prepared, jointly with CBER, a requested draft document for the CDRH Center Director on the risk of transmitting TSEs through medical devices and products with components of bovine origin;
  • Prepared, through a joint CDRH/CBER.CDC Working Group, draft recommendations on the decontamination and sterilization of medical devices exposed to the CJD agent;
  • Developed (with CBER) guidance for industry on preventive measures to reduce the possible risk of transmission of CJD and vCJD by human cells, tissues, and cellular and tissue-based products; and
  • Educated Center/Agency staff and scientific communities using presentations and publications.

DEHP Safety Assessment

Key words: DEHP, risk assessment, medical devices, PVC

Patients undergoing various medical procedures can be exposed to di-(2-ethylhexyl)phthalate (DEHP), a compound used as a plasticizer for polyvinyl chloride (PVC) medical devices. Since exposure to DEHP results in the development of adverse effects in experimental animals, OST conducted a safety assessment (http://www.fda.gov/downloads/MedicalDevices/ DeviceRegulationandGuidance/GuidanceDocuments/UCM080457.pdf) to determine the likelihood that patients exposed to this compound would experience similar effects. The results of the safety assessment suggest that children, especially male neonates, undergoing certain medical procedures may represent a population at increased risk for the adverse effects of DEHP. Based on the results of the safety assessment, CDRH issued a consumer update (http://www.fda.gov/MedicalDevices/ ResourcesforYou/Consumers/ChoosingaMedicalDevice/ucm142643.htm) to inform the public and health care professionals of the potential risks posed by patient exposure to DEHP released from medical devices.

Studies on Reuse of Single-Use Devices

Key words: reuse, single-use devices, cleaning, disinfection, reprocessor, ethylene oxide, sterilization

In FY 2001, scientists continued to study the issues of cleaning medical devices to establish their safety and efficacy for reuse. A major part of the study addressed detecting and cleaning the lubricating oils from medical devices. A second major part of the study addressed the use of disinfectants in cleaning processes. Disinfectants, other than bleach, make cleaning difficult and also provide some false information on cleaning strategies. These data have been used in formulating CDRH regulatory actions, establishing criteria for review of PMA's and 510K's, and providing methods for the Office of Compliance to inspect reprocessor firms. Scientists have completed studies of the amount of ethylene oxide, (a common sterilant) residues in medical devices placed under various experimental conditions, such as multiple exposures, differing extraction conditions, and differing extraction media.

Endotoxin-Mediated Potentiation of Toxicity: Implications for Reprocessing and Reuse

Key words: endotoxin, reuse, potentiation of toxicity, medical device materials, ISO 10993-17

Patients can be exposed to bacterial endotoxin following the use of improperly reprocessed medical equipment. Such exposures can have clinically significant consequences since endotoxin has been shown to potentiate the adverse effects of a number of chemical compounds that could be released from medical devices. In FY 2001, OST initiated laboratory studies to determine the extent to which endotoxin potentiates the toxicity of specific compounds released from devices. In addition, OST staff examined whether the approach described in ISO/DIS 10993-17 to set allowable limits for compounds released from devices is sufficient to protect critically ill patients from chemically induced adverse effects.