FY 2005 OSEL Regulatory Support Activities
The two primary functions of the Office are:
- Strategically managed research with the aim of providing a scientifically sound basis for responding to current challenges and anticipating future regulatory challenges, and
- Provide technical consults in support of the Center’s pre-market and post-market activities.
Both activities are coordinated within OSEL in an effective manner so as to best meet the Center’s regulatory and science needs. The strategically managed research of the Office is described in subsequent sections in great detail. This research activity is the cornerstone upon which the Office provides the regulatory support function. The laboratory research is largely based on investigations related to the mechanistic understanding of the device performance or test procedures to enable the Center and device manufacturers to gain an improved understanding of issues related to the safety and efficacy. In general, though the research is directed toward issues identified at the pre-market approval level, in reality, the research has the major impact on the post-market end of the Center’s business because most often the research is anticipatory in terms of potential issues of medical devices identified at the pre-market level.
The regulatory support function of the Office is provided through consults in support of both pre-market decisions and post-market actions using expertise developed in the laboratory. A consult is a request for expert advice or information of a specific nature, where it is perceived that expertise is more discipline related than medical device related. Consult provides information which contributes to sound regulatory decisions. Consults may be based on acknowledged scientific/engineering principles or on independent data generated in OSEL laboratories.
The following provides a consolidated picture of the breadth of consults that OSEL provides to Center’s offices in 2005:
Number of consults to pre-market issues: 1023
Number of consults to post-market issues: 173
Number of consults to other Centers and agencies: 60
Number of activities related to standards: 116
The information provided by a consult is used in some of the following ways:
- evaluating a pre-market submission (IDE, HDE, PMA, 510(k)),
- supporting a compliance action (regulatory case support/development, Health Hazard Evaluation, Health Risk Assessments, etc.),
- assisting in a scientific collaboration,
- answering a consumer inquiry,
- providing opinions on guidance documents,
- providing edits to one pagers for the new device approval page,
- assisting in health hazard evaluation/health risk assessments or in device determinations/classifications.
In many post-market as well as pre-market regulatory issues, OSEL reviews and investigations may provide an independent assessment of claims made by a manufacturer or other party concerning safety or effectiveness. In other cases, OSEL reviews may assess the adequacy of a design, a failure investigation, a production process, or a quality process employed by the manufacturer. These reviews and analyses rely on in-house expertise and are often augmented by expertise solicited from colleagues in academia, other government laboratories, or even other industry sectors. OSEL laboratory investigations may be undertaken in instances where the veracity of a performance claim needs to be independently verified by testing, or when the claimant lacks the resources to conduct the investigation. Specifically, OSEL provides analytical support to post-market regulatory activities in a variety of ways:
- Scientific and engineering reviews and analyses
- Laboratory investigations of product performance
- Participation in inspections of medical device establishments
- Forensic reviews and investigations
- Identify device safety and performance issues
- Provide training to FDA and industry
- Contributions to Center-wide teams on issues identification as well as science- based analysis of post-market device performance
Standards and measurements are important products of this office. OSEL provides innovative solutions to public health problems through the development of generic techniques that lead to national and international standards to enhance product safety and effectiveness. A major activity related to standards is staff participation in standards development at the national as well as international level by conducting research to develop standard procedures and by managing, developing, and supporting standards used for regulatory assessments.
The following is an illustration from the past of a regulatory support activity in which OSEL participated. A few years ago, the reuse of single use devices was a major issue. OSEL established a major research project on this issue in response to a request from the Office of Compliance and Office of Surveillance and Biometrics to address issues related to reuse of single use devices. OSEL researchers organized a team and initiated a preliminary study to determine the effects of a variety of disinfection and sterilization methods on variety of generic materials. The team worked with other Center Offices to set up a retrieval program of cardiac catheters after single use at two local hospitals. These catheters were marketed for single use only but were reprocessed for reuse in many hospitals and third party facilities. To identify the nature and scope of potential problems with reuse of these devices, the team identified key performance characteristics and developed laboratory test methods to study the effects of use and simulated reuse on these characteristics. OSEL also developed methods for simulating reuse. The laboratory data demonstrated that the performance of some devices does not meet manufacturers’ specifications after a single use, and that these properties are further altered after simulated reuse, re-cleaning or resterilization. These laboratory data have had a major impact on the Center's deliberations on the subject as well as incorporation of the data in standards development.
The following examples illustrate the depth and breath of OSEL consults:
1. Computational fluid dynamics of left ventricular assist device
OSEL laboratory expertise in experimental and computation fluid dynamics was recently utilized to aid in the evaluation of a post-approval study change for a pediatric left ventricular assist device (LVAD). The sponsor proposed to make a change to the blood flow path within the pump that could have adversely affected hemolysis and thrombogenesis in the pump such that patient safety and/or device efficacy could have been compromised. It would have been extremely difficult, if not impossible, to validate the design changes using animal or human data. After discussions and a meeting with FDA staff, the sponsor agreed to provide experimental (flow visualization, hemolysis) and analytical (computational fluid dynamics [CFD]) testing to support the design changes. CDRH experts recommended appropriate CFD models to the sponsors and analyzed the results. In this instance, our efforts eliminated the need for the sponsor to perform expensive and time-consuming animal testing and/or clinical testing. The proposed design changes were approved, thus expediting the availability of this innovative device.
2. Computer-assisted diagnostic systems
OSEL scientists have also played a leading role in the development of new models and methods for the assessment of computer-assisted diagnostic systems. The techniques were first developed during our review of digital mammography systems, and have since been extended to the development of systems for breast cancer screening, lung cancer screening, and CT colonoscopy. CDRH scientists who have developed these methods have played an important role on the review team for applications for these devices. Having these tools and methods available has greatly assisted developers of these innovative imaging and CAD-assist devices.
3. Performance testing of pulse oximeters
CDRH scientists and engineers have developed test methods for a range of non-invasive monitoring devices. CDRH laboratory studies on pulse oximeter performance, for example, enabled substantial improvements in the ISO/IEC standard and the CDRH Guidance Document. This testing facilitated the development of a single test protocol for SpO2 accuracy studies, which simplified the pre-market evaluation process by unifying the basis for establishing substantial equivalence. The work has established the groundwork to enable the extensions of claims being made for perfusion measurements and established acceptable performance criteria. In a related initiative, CDRH laboratory work on surface temperature properties was central in defining the limits for the General Standard for Electromedical Safety, 3 rd edition of IEC 60601-1, and for the particular standard for the safety and essential performance of pulse oximeters, ISO/IEC 9919. CDRH laboratory scientists, working with industry experts, provided computational models and relevant literature that established that the existing limit could be relaxed by 2°C, making possible new device types and extending applications of existing devices. CDRH laboratory efforts were also instrumental in the establishment of a reliable test method for validating the design of pulse oximeter cables. This work is being incorporated in the next revision of the ISO/IEC standard.
4. Test methods for high intensity focused ultrasound
CDRH is receiving increasing numbers of regulatory submissions for high intensity focused ultrasound (HIFU) surgery. HIFU holds the potential for radically advanced surgical techniques, including ablation of both malignant and benign lesions and cessation of internal bleeding in injured vessels and organs, all with minimal damage to the surrounding tissue. However, the lack of standardized methods to assess the acoustic and thermal characteristics of the focused beams has challenged the regulatory review of these devices, especially in the pre-clinical phase, and has been burdensome to the industry. In the past CDRH scientists and engineers have developed measurement instrumentation and computational modeling techniques for characterizing other types of medical ultrasound devices such as diagnostic imaging and therapeutic ultrasound, and this work has resulted in the creation of numerous regulatory guidance and standards documents. This expertise is being used to accelerate the review of submissions for HIFU devices. For example, in a device for the ablation of uterine fibroids, CDRH-developed computational modeling was used to predict the performance of the device under conditions that would have been difficult to investigate experimentally, thus shortening the review time. CDRH laboratory staff members are now collaborating with outside research institutions and the affected industry to develop standard measurement and analysis methods as input to international standards for HIFU that will be used to facilitate the regulatory review process.
5. Guidance for extracorporeal shock wave lithotripsy
Extracorporeal shock wave lithotripsy is a minimally invasive technology that employs focused, high pressure ultrasonic waves for fragmentation of kidney and ureteral calculi. When first introduced, these devices were deemed Class III because of the new intended use coupled with the potential for serious collateral damage to non-targeted tissue. At the time there were no accepted means for measuring the very high pressures produced by these devices, which complicated the regulatory reviews. Based on CDRH laboratory efforts, performance requirements for measurement instruments and appropriate measurement procedures were developed and documented in a pre-clinical testing guidance for the industry. This guidance eventually led to two international consensus standards, which in turn were instrumental in allowing CDRH to down-classify these devices to Class II, thus saving the industry from lengthy human clinical trials.
6. Expediting intraocular lens evaluations
OSEL laboratory scientists have played a leading role in the development of new test methods for measuring the optical parameters of intraocular lens implants (IOLs). An estimated 20 million Americans over the age of 40 have cataracts in at least one eye, most of which can be corrected through the implantation of IOLs. The focal length (or dioptic power) is a fundamental parameter whose precise measurement is of critical importance for evaluating the safety and effectiveness of IOLs. Testing the dioptic power of IOLs has been difficult because conventionally used test methods are limited in terms of accuracy and the dynamic range over which measurements can be performed. To overcome these problems, CDRH laboratory scientists developed a novel confocal fiber-optic laser method (CFOLM) for precise measurement of IOL dioptic power which provides high accuracy (exceeding 1 um) in spatially locating the focal point and in measuring the IOL dioptic power. Such accurate measurements have not been achievable previously. The new CFOLM measurement system has been used to evaluate the dioptic power of a variety of new IOL designs from several different manufacturers, and to resolve questions about the accuracy of the labeled dioptic power, expediting decision making by facilitating agreement between industry and CDRH. This new test method will be considered for incorporation in international product performance standards for testing IOLs.
In addition, experimental and theoretical work in the laboratories on the mechanism of formation of vacuoles in foldable, hydrophobic intraocular lenses (IOLs) has led to an understanding of differential osmotic forces as the root cause of these artifacts. Characterization of the kinetics of vacuole formation revealed that changes in the lens environment (both thermal and chemical) can modulate the size and number of vacuoles. These observations allowed for the rapid acceptance of changes in the storage solutions proposed by the sponsors of a new class of hydrophobic IOL materials. The computational and experimental tools developed in these studies will allow for rapid evaluation of optical stability of future classes of IOL materials.
7. Spinal implant evaluation
FDA has received a dramatic increase in the number of submissions for new spinal implants, a sector of the orthopedic medical device industry whose revenues were estimated at $3.6 billion in 2005, signifying an increase of 17% over the previous year. Motion-preserving devices and novel concepts such as minimally invasive fracture repair strategies have been responsible for much of this growth. Under the auspices of MDUFMA, CDRH laboratories initiated a research program into vertebroplasty, a minimally invasive procedure for treatment of spinal compression fractures, with the goal of providing reviewers with better scientific information on the mechanical benefits of the treatment in order to accelerate and improve reviews of product safety and labeling. This laboratory initiative resulted in developing information clarifying the mechanical stability of the spine after this treatment which has substantially assisted CDRH's scientific review staff, enabling more efficient interactions with manufacturers and expediting the review process. CDRH laboratory staff have also become active participants on CDRH's spine review team as well as an international standards organization that writes standard testing methods for medical implants, ASTM F04 Medical & Surgical Materials and Devices. In fact, CDRH laboratory staff have assumed the chairmanship of the ASTM subcommittee F04.25 on spinal devices. In addition, CDRH laboratory scientists have provided the device reviewers in CDRH's Office of Device Evaluation with information on the use of these testing standards which, complemented with physical models of testing fixtures, has enabled improved understanding of how standard test methods are being used by device companies. This understanding has greatly facilitated their reviews of new products.