Abstract
This is an exceptional, first edition, book and a significant undertaking by the author and his collaborators. As is laid out in the first chapters, the book is an introduction to the complex arena of meeting regulatory requirements for safety testing of medical devices. Medical devices are almost as old as the history of medicine, yet Gad has prepared a relatively succinct summary of the regulatory and safety assessment of devices in general, with specific examples included as supportive information.
Chapters 1 and 2 of the book provide an exemplary review that coalesces the regulatory and safety rationales and assessments of devices. These are useful/important for the novice and the experienced regulatory or toxicology professional.
Chapter 3 provides, initially, a summary of the ISO 10993 guidelines for assessment of the safety of medical devices. That summary is followed by details of the various International Organization for Standardization guides for the different types of tests, the rationale for those tests and how they are applied for different types of devices. Important to this chapter is the presentation of alternative test methods in addition to the “standard” tests. Chapter 4 addresses the different methods that are recommended/available for test sample preparation—extraction and leachates—and when these are appropriate for different types of devices. Important to this chapter is a detailed discussion of the analytical methods that can be used for assessing and quantifying the identity of compounds in extracts or leachates.
Chapter 5 does a particularly good job of discussing where to find published or historical safety data for individual compounds that have been identified in the leachates/extracts. Jumping ahead, Chapter 8 probably should follow Chapter 5 as it addresses what can be done if there are no, or insufficient, safety data in the literature. Chapter 8 discusses the rationale and details of methods for quantitative structure activity relationship assessments, or QSAR, of compounds identified in leachates/extracts when there are little or no safety data available. Quantitative structure activity relationship, as we know it, is a methodological means for saying that a particular identified compound has components that are structurally related to compounds of previously identified toxicologic properties. These can, therefore, be presumed to have similar/related toxicologic properties. Several of the QSAR methods or procedures are described in detail.
Chapter 6 brings in an important topic and that is discussing the relationship between dose—use route for a device under actual use versus the dose—route that is used for safety evaluation in in vitro or in vivo tests. The various international regulatory guidelines are presented, and their attributes and deficiencies are discussed.
Chapter 7 addresses the goal of the risk assessment that is derived from the analytical and biological and QSAR data that have been generated. There are several approaches, depending on the device, use, exposure duration, nature of the safety data that are available and so on. The goal, of course, is to use the available data to establish a best estimate assessment of the safety risk to patients who would be exposed to the device in question. The chapter addresses this complex subject in a straightforward manner so that the reader understands the different means for addressing the issue.
Chapter 9 presents the issue of how pathology and histopathology associated with actual or simulated use of a given device will impact the overall safety evaluation of the device. In vitro tests and analysis of extracts and leachates can tell us much about the probable safety of the device. Evaluation under actual use simulations can yield valuable data and for such evaluations the pathology and histopathology are critical. The chapter describes and discusses the methodologies and processes for the inclusion of these types of data in the safety evaluation.
Chapter 10 addresses the challenges of the use of “nanomaterials,” these are devices that range in size from 1 to 100 nm. The term includes a range of types and shapes of materials and a variety of compositions. These are frequently used as carriers for medications, but the range of applications is much wider. The chapter does a good job, in a short space, of describing the nature of nanomaterials (or nanoparticles), the regulatory approaches to determination of their safety and the technical methods that are frequently applied. Safety assessment may be complicated by the actual use—does one evaluate the safety of a nanomaterial alone or a nanomaterial that is, for example, carrying drug to a target organ or one that is easily biodegradable versus one that is not? The chapter does a commendable job of presenting the current difficulties with singular regulation of the wide variety and numbers of applications for these types of devices.
Chapter 11 summarizes the salient points and issues of the preceding chapters and, rightfully, points out that there is no one set of tests that assure safety of any device. Further, it is shown to be imperative that, if a risk assessment is to be robust and effective, it should include data from a spectrum of biological, bioanalytical, and mathematical models. Underscoring the details of guidance and test procedures in the preceding chapters, the author affirms that the methods that are applied must depend on the nature of the device, its proposed application and duration of use as well as the prevailing science at the time.
Chapter 12 presents an overview and discussion of the major classes of materials that are used in manufacturing devices—polymers, metals, glass, and ceramics. The chapter also discusses the plethora of variations in materials within these groups, and the complexity of device composition that can be found. This again emphasizes the need to tailor the safety determinations to the type of device and the proposed use(s) of the device.
The presentations in Appendices A and B are quite useful in pointing out where one can go for carrying out safety/analytical QSAR testing of a device or related data and for pointing out the various global regulatory agencies. The latter may be more durable than the former as Contract Research Organizations are a bit more fluid or limited in the types of work that they do.
This book is an exceptionally good compendium of information ranging from what is needed on the route to determining the safety of devices and how to get to the goal of providing safe devices for use in patients. The detail provided in each chapter applies and appeals to a variety of technical and regulatory audiences. It is clear, also, that the author and his collaborators recognize, and emphasize, the need to interface with the domestic or international regulatory authorities during this process. This book would be helpful to graduate students pursuing a program in regulatory toxicology or to anyone engaged in the practical aspects of evaluation of the safety of medical devices.