FY 2006 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 needs and anticipating future regulatory challenges, and
- Provide technical consults in support of the Center’s pre-market, post-market, and compliance activities.
Both activities are coordinated within OSEL in an effective manner so as to best meet the Center’s regulatory 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 device performance or test procedures to enable the Center and device manufacturers to gain an improved understanding of issues related to safety and efficacy. In general, although the research is directed toward issues identified at the pre-market approval level, the reality is that 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 OSEL consults in 2006:
Number of consults to pre-market issues: 1159
Number of consults to post-market issues: 213
Number of activities related to standards 353
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; and
- 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 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:
- Provide scientific and engineering reviews and analyses;
- Conduct laboratory investigations of product performance;
- Participate in inspections of medical device establishments;
- Conduct forensic reviews and investigations;
- Identify device safety and performance issues;
- Provide training to FDA and industry; and
- Contribute 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 examples illustrate the depth and breath of OSEL consults:
Division of Biology
Bioeffects and Toxicology of Nanomaterials: Nanotechnology has great potential for medical applications and presents FDA with an emerging area of clinical products for regulatory review. In spite of remarkable advances in the use of nanomaterials, there is a paucity of knowledge in understanding the toxicology of nanomaterials. Properties of nanoparticles, such as small size, large surface area, and high reactivity that make them unique and impart tremendous potential for technological advances, are also the very properties that may be responsible for adverse effects.
Several recent government and independent reports, and a Citizen Petition, have raised concerns as to whether the FDA has the appropriate regulatory framework, including standardized methods, to properly assess the safety of nanomaterials-based medical products. If nanotechnology is to fulfill its enormous potential for development of FDA-regulated products, it is critical to understand if patients are at an increased risk from exposure to nanomaterial-based medical products. FDA and CDRH do not have a regulatory framework to explicitly address pre-market or post-market issues with nanotechnology-based medical devices. CDRH scientists are conducting targeted research to develop a framework to evaluate the safety of nanotechnology-based medical devices, both those already approved (post-market) and those under development and early in the product life cycle (pre-market). A better understanding of relationships between physicochemical properties of nanomaterials and adverse effects will enable CDRH to determine if new safety test methods and protocols are needed to move nanomaterial-based medical products forward from preclinical and clinical development to the bedside. CDRH laboratory scientists have established research collaborations with outside research institutions to establish and/or refine methods for assessing the potential adverse effects of nanoparticles used in medical products, and to develop consensus standards to facilitate the regulatory review process.
Division of Chemistry and Materials Science
Scientists in the DCMS Laboratory for Active Materials have been focusing on the effect of processing variables on the rate of release of therapeutics and on the morphology and surface characteristics of model stent coatings. These results have led to a better understanding of the relationship between changes in processing temperature and the resultant changes in drug release rates. The knowledge gained from this work has enhanced our ability to ask crucial questions regarding manufacturing issues. Specifically, these results have recently been used in support of review of PMA supplements for manufacturing changes (ODE/DCD) where the sponsor requested a change of processing temperature of their coating procedure. Finally, recent issues regarding late stage thrombosis has led the lab to focus some of its attention on the changes in surface roughness and topology as drug elutes which may be a contributing factor to these issues.
Division of Electrical and Software Engineering
NIH FOX Study: OSEL medical device engineering expertise was used to support the NIH Fetal Oximetry Trial that provided the major component of a post-market approval study plan for the Nellcor intrapartum fetal pulse oximeter when it was approved in May 2000 (P990053). An OSEL systems engineer collected clinical requirements from 14 clinical sites ranging from large university hospitals to smaller rural clinical centers. Based on these requirements, OSEL engineers developed a personal-computer-based data acquisition system using a custom-modified fetal oximeter provided by Nellcor and maternal-fetal monitor provided by Corometrics. Following design validation, the system was deployed to all 14 sites and ultimately used to acquire data from 5,341 women. The data was analyzed by the NIH team with the definitive conclusion that the device had minimal effectiveness. The product was subsequently withdrawn from the market by the manufacturer. The study results were published in the New England Journal of Medicine in November 2006.
Software Forensics Lab: The analysis of medical device software to detect design defects has traditionally involved laborious manual review of the source code. The enormous size of modern software applications make such manual review practically impossible. In recent years, advances in processing power and mathematical modeling have enabled the development of static and dynamic analysis tools that allow an analyst to quickly isolate a wide variety of software design defects, from poor workmanship to inadvisable design practices and even to the types of errors which could not normally be found even by rigorous testing. However, a high degree of skill and experience is required to use these tools successfully.
The Software Forensic Laboratory located has been consulting with other federal agencies involved with software integrity issues, including the DOD, FBI, NIST and NASA, and has leveraged the latest academic research to implement a state-of-the-art software forensic capability during 2006. This capability may be used in any phase of the product life cycle, but is particularly valuable in understanding the root causes of adverse events due to software failures. We believe that this science-based capability is found nowhere else in the federal regulatory environment.
In 2006, this new capability was used to the great benefit of the Center in several high-profile compliance cases. Ultimately, such tools will increasingly be used by medical device manufacturers in their own product development phase, thereby reducing the frequency of software defects and the incidence of adverse events and product recalls.
In 2007, the Software Forensics team plans to acquire more tools for reverse abstract modeling of embedded system software thought to be responsible for a medical device adverse event, and an ongoing goal of the team will be to improve its response time and throughput.
Division of Imaging and Applied Mathematics
Performance Assessment Accounting for Reader Variability in Medical Imaging Diagnostics: The OSEL Division of Imaging and Applied Mathematics (DIAM) has a strong history in researching clinical study design and performance assessment methodologies. This research is critical to characterizing diagnostic devices of all types, and specifically, to evaluating the use of imaging devices by physicians in the field. Interpretation of images by physicians is perhaps the weakest link in the diagnostic process, involving a lot of reader variability. Therefore, scientific evaluation of diagnostic imaging devices requires tools needed to estimate and understand reader variability and the interaction of the reader and the device. The field where these tools are being developed is often referred to as Multi-Reader, Multi-Case (MRMC) variance analysis, and several key contributions to this field have been made by several of DIAM scientists.
Dr. Brandon Gallas provided a consult in 2005 on a diagnostic imaging device for the ODE Division of Reproductive, Abdominal and Radiologic Devices (DRARD), Obstetrics and of Gynecology Devices Branch (OGDB): the LUMA™ Cervical Imaging System by Medispectra Inc. During his review, Dr. Gallas pointed out that the variance assessment did not account for reader variability, a subject that he encountered during his Ph.D. work and one that he was vigorously studying with his colleagues in DIAM. However, in the complicated world of device review, reader variability was not a high priority: the issue had never been mentioned to the sponsor during early meetings on the pivotal study protocol, and no one had a ready-to-go method to account for reader variability according to the sponsor’s study design.
Since (and during) that review, Dr. Gallas developed a new MRMC variance estimation tool for AUC according to a fully-crossed study design: AUC denotes the area under the Receiver Operating Characteristic Curve (ROC) and is a diagnostic performance metric; a fully-crossed study design is one in which every doctor diagnoses every patient. While AUC is an extremely useful measure of diagnostic performance and the fully-crossed study design is a statistically efficient use of cases, the strategy may not be practical for all sponsors. Another, perhaps more common assessment strategy taken by sponsors, is to estimate sensitivity and specificity according to a doctor-patient study design (doctors diagnose only their own patients). Thus, Dr. Gallas has generalized his MRMC variance estimation tool to this strategy and other common reading protocols. This newly developed analysis methodology has already been employed in the review of Fuji Computed Radiography Mammography Suite. OSEL anticipates this becoming part of the analysis for devices that depend on a physician interpretation of the device outputs.
Division of Physics
Analysis of Electrosurgical Unit Ground Pad Heating: The OSEL Division of Physics (DP) has an extended history of investigating thermal injury and heating issues associated with low frequency electromagnetic devices. This research is a critical cross-cutting area for premarket and postmarket review of all types of radiofrequency ablation, hyperthermia, and other thermal therapy devices. Research work and computational analysis have played an integral part in the development of standardized test methodologies and relevant regulatory standards and were recently applied to the analysis of electrosurgical unit ground pads. Ground pads (dispersive electrodes) are commonly used for all classes of radiofrequency ablation products in addition to its uses for electrosurgery. In July 2005, a post-market issues (PMI) group was convened to address adverse events resulting from severe burns (2nd and 3rd degree) located at the ground pad sites. Each year, CDRH receives over 650 adverse reports related to ground pad burns
Dr. Isaac Chang was the OSEL representative to the PMI action team. He provided an extensive analysis that demonstrated that the standardized test methodology used to approve ground pads was flawed. According to AAMI HF-18 and IEC601-2-2, the temperature beneath ground pads under testing conditions should not exceed 6ï‚°C and should have an impedance that does not exceed 75 ohms. The standard test methodology, assesses these two attributes separately. Dr. Chang developed computational tools to assess the thermal and electrical problems simultaneously and found that electrodes with identical electrical characteristics could differ in the maximum temperature rise by as much as 10 degrees C; which may explain why identical ground pad specifications resulted in skin burns in some cases, and not in others. In 2006, Dr. Chang expanded his computational studies to test over 815 different ground pad configurations under the AAMI HF-18 test conditions on an anatomically correct rendering of a human male model (based on MRI images) at 5 cubic millimeter resolution. The developed model is the first whole-body computational model that simultaneously solves the electric field, temperature distribution, and predicts thermal injury with over 32 million degrees of freedom. Graphics tools were developed to allow plane-by-plane analysis, which allowed Dr. Chang to visualize not only topical skin burns, but thermal injury to subdermal tissues as well. He experimentally verified his findings under in vitro and in vivo conditions and validated the results of his computational analysis. Dr. Chang documented the results in a 65-page white paper, which was distributed to each office in CDRH.
As nearly all devices using a return ground pad employ an impedance cutoff as an emergency shutoff feature, Dr. Chang’s results indicated that hundreds of medical devices may be affected by these findings. Worse still, the AAMI HF-18 and IEC601-2-2 standards are an integral part of pre-market review since they are the primary electrical safety standards used by CDRH for all high frequency medical devices. Dr. Chang worked with the standard’s coordinator for both standards in October 2006 and submitted recommendations to modify the test methodologies. He is currently in the process of publishing his findings to raise the level of awareness of this problem in both the clinical and manufacturing communities.
Division of Solids and Fluid Mechanics
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, one challenge to testing HIFU devices is the lack of suitable tissue-mimicking materials that not only have tissue-like acoustic and thermal properties, but also can withstand the intense acoustic fields without damage. CDRH laboratory staff members have developed and tested a gel-based material with the requisite properties. This work has been leveraged by funding under an interagency agreement (IAG) from DARPA, which has interest in HIFU test bed development because of a project to develop a HIFU system for treating battlefield wounds. This research, as well as other laboratory products, is being used as input to international standards that are under development for HIFU. These standards will help expedite the regulatory review process.
MRI Safety and Compatibility of Implants and Medical Devices: Millions of patients undergo MR imaging each year. Unfortunately thousands of patients who would benefit from the information gained via MRI cannot undergo the procedure because they have electrically active implants like pacemakers that can fail or malfunction in a MRI scanner. This danger became clear to CDRH when in 1992, a woman with an intracranial aneurysm clip was killed as she was brought near an MR scanner in preparation for an MR examination. The aneurysm clip was moved by the magnetic field, tearing the clipped artery and killing the patient. CDRH has been actively involved in assuring the safety of medical devices within MRI scanners since that first fatal accident. For example, under OSEL leadership, ASTM has now published four standard test methods for determining MR safety and one method for marking devices for safety in the MR environment. These are the only existing standardized test methods for determining MR safety of medical devices. This past year OSEL has made a number of contributions to expand the standards to apply to electrically active implants and equipment. In particular, OSEL is working the international MRI community to more appropriately address RF heating of active devices during MRI. Significant short-comings in the ASTM testing protocols were identified and are being addressed. These short-comings are most significant for electrically active implants with their inherent conducting leads and wires. OSEL is continuing its activities in this area and is now actively working with both ISO and IEC to address problem of MR compatibility with implants.
Corrosion testing: In 2006 OSEL scientists helped conduct the first round robin validation tests for corrosion resistance of small devices such as stents. This test method, known as ASTM F2129, has become one of the most referenced standards for cardiovascular stents, particularly those made of Nitinol. Nitinol is a metal increasingly used for metal components of implants because it is typically strong, light, and very inert, with a very high corrosion resistance. However, this corrosion resistance depends upon the final condition of the Nitinol surface and can be inadvertently destroyed. CDRH became aware of this unexpected property of Nitinol in the late 1990’s while reviewing the corrosion testing data on several Nitinol stents that showed a high corrosion and pitting rate. This result was surprising, since from past experience with the alloy, a very low corrosion rate would be expected. CDRH scientists then conducted laboratory tests and observed similar high pitting corrosion rates. CDRH scientists then drafted F2129 and worked with ASTM to get this standard approved and recognized. It was accepted almost immediately as the best available protection for implanted devices against undesired failure from corrosion. CDRH and industry worked together via the ASTM standards process to revise and refine the method and this year a formal evaluation round-robin test was conducted, with OSEL as one of the 12 participating laboratories. To everyone’s relief, the data were in reasonable agreement. OSEL continues to be active in the further evaluation of this most important standard.