Abstract
Chapter 1—Safety Evaluation of Medical Device
This chapter provides a general overview of medical device safety considerations with a focus on biocompatibility. The history of medical device regulation is geared toward an audience who has limited understanding of the overall regulatory pathways and touches on only the major pieces of legislation. The authors do not reference Food and Drug Administration’s (FDA’s) database containing guidance documents that offer the agency’s current thinking on various technical topics relating to medical devices and safety issues. Although these documents do not constitute regulation per se, the content supplements the statutes and regulations by sharing the agency’s current thinking on the subject matter. Finally, the author indicates that medical devices are regulated by the Center for Devices and Radiological Health; however, the Center for Biologics Evaluation Research is responsible for reviewing blood-related devices and some in vitro diagnostic devices. Little information is provided on how combination products are regulated and nothing is included regarding the role that the primary mode of action plays in the Office of Combination Products’ decision on the lead center designation. In general, this chapter provides the reader with a very general overview of the medical device regulations.
Chapter 2—Regulatory Aspects and Strategy in Medical Device and Biomaterials Safety Evaluation
The regulatory basis covering medical device safety testing is generally summarized in this chapter. On page 11, the author states that US regulations are derived from 7 principal laws, but items 6 and 7 in the list are not regulations. One is a guidance memo from FDA and the other is International Standards Organization (ISO) 10993 (2013). The review times presented on page 13 are not current (There are more authoritative references on FDA review statistics than the gray sheet such as the Center for Device and Radiological Health’s (CDRH)’s Medical Device User Fee and Modernization Act (MDUFA) reports submitted annually to Congress). The description of “de novo” is somewhat misleading in that a device not having a legal marketed predicate, one for which FDA has not previously classified or published a regulation and/or one that can be demonstrated to have a low to moderate risk, may be eligible for de novo review. Only after a de novo submission has been reviewed and accepted, FDA will issue a substantial equivalent concurrence letter. Under the section, regulation versus law, there is an incorrect citation of the location of the PMA regulation. The premarket approval regulations are found in 21CFR814 (not 312). On page 14, the reference to Classification of Devices is incorrect for class III. Class III premarket approval is truly an FDA market approval for a high risk device, and the reference to “clinical use only” is in error and misleading. Table 2.1 listing the characteristics of a class I device seems to be “over kill” since there is little information provided on class II and class III devices, which required an ever increasing level of regulatory control. The mandatory role and function of United States Pharmacopeia (USP) is somewhat misleading as it pertains to medical devices. Other standard organizations such as American National Standards Institute and other voluntary standards are accepted with the FDA review of medical devices. The chapter contains several summary tables and flowcharts showing how various regulatory bodies including FDA view biocompatibility testing requirements. Each of these are based on ISO 10993-1 requirements. Tables showing differences in test procedures are helpful to individuals seeking to develop a testing plan. The authors provide a high-level summary of the European Conformity (CE) marking process with a focus on the biocompatibility testing requirements. The chapter includes some examples of case studies, which help the reader better understand the basic testing issues. If the authors had incorporated some of FDA’s guidance documents, perhaps a clearer understanding of the concept of safety margin may have been provided, especially in the area of risk assessment and mitigation. Nonetheless, this chapter provides the reader with a general overview of the most significant safety-related issues when testing medical devices and biomaterials.
Chapter 3—Road Maps to Test Selection
This chapter addresses key concepts to consider when selecting a battery of tests that may be required to obtain regulatory clearance for a new medical device. The section on chemical and physical property considerations is very good. This is an excellent reference summary that is informative for design engineers, quality personnel, and regulatory affair professionals. The section addressing factors influencing test selection is quite good for individuals new to the industry and as a refresher for experienced research and development (R&D) personnel. The chapter offers many tables that summarize multiple issues associated with selecting and interpreting tests. Once again, FDA has issued many device-specific guidance documents that present the agency’s interpretation of regulations and testing expectations for special types of devices. If the authors had incorporated these references into the text, the chapter may have been of greater help to the novice reader. The reference list at the end of the chapter is very good.
Chapter 4—Materials in Medical Device Design
The authors provide a very good overview of the major types of materials commonly used in designing and developing medical devices. The discussion on metals is good since it captures the pros and cons of various materials when chosen for use in medical devices. A brief discussion on ceramics and glasses includes tables summarizing properties and commonly used materials. The section on polymers is more in depth, and the authors summarize key characteristics of common polymers. Synthetic organic polymers are of greatest interest to medical device developers. A section on textiles covers those most commonly used types primarily for wound dressings and personal protective equipment and less commonly in surgical applications. This chapter provides some very useful table on color additives used in medical devices. There is a very short discussion of nanomaterials. This chapter provides a nice foundation for addressing biocompatibility issues presented in other chapters. Once again, the authors provide an extensive list of references supporting the content of this chapter.
Chapter 5—What to Test Sampling and Sample Preparation
The focus of this chapter is on issues associated with how to actually perform tests. The content of this chapter builds on information present in chapter 3. The author includes some insightful guidance both on choosing the sample size as well as the technical aspects of preparing test samples for evaluation. There is heavy reference made to ISO-10993-12 throughout the section. A brief discussion addressing some of the statistical consideration for sample size, sampling techniques, and randomization is provided. Technical information pertaining to sample preparation is summarized in a series of tables, which are easily referenced by the reader.
Chapter 6—Cytotoxicity Testing
In the medical device industry, cytotoxicity tests are primarily used for screening the biomaterials and finished medical devices using mammalian cell cultures. Therefore, the test results are used for assessing biocompatibility in conjunction with other tests. The authors provide an interesting historical summary of the various types of tests including crystal violet staining, silicone microphysiometer, Microtox test, agar diffusion test, elution test, and others. The authors caution the reader about correlation of test results directly with in vivo results due to high levels of false negatives and false positives. The authors do not include any of the FDA guidance documents pertaining to biocompatibility testing of medical devices in this chapter. Perhaps, this would provide the reader with a better understanding about how such tests can be used to support medical device marketing applications.
Chapter 7—Hemocompatibility (ISO 10993-4)
From an FDA viewpoint and among other regulatory bodies, hemocompatibility of medical devices that have direct contact with circulating blood is of vital importance to demonstrating the safety profile of a device. The ISO standard contains some 25 different categories of assays for evaluation. The authors provide an insightful discussion of the challenges of testing and interpreting results when arterial and venous blood samples are tested. This chapter addresses 5 key end points that FDA commonly expects to see in submission, which include thrombosis, coagulation, platelets, hematology, and immunology. Table 7.1 provides an excellent summary of tests that should be considered for use with medical devices that contact human blood. Table 7.2 provides a list of standard tests along with abbreviations and description, which may be very useful to a reader who has limited background in choosing hemocompatibility tests.
Chapter 8—Local Tissue Tolerance
This chapter presents a summary of tests associated with assessing local tissue tolerance or irritation in the immediate region of the medical device’s contact with tissue. A very good overview of the primary dermal irritation test is provided along with details for interpreting the results of tests. Tables are included for easy reference by the reader. Ocular irritation testing including in vitro alternatives is presented. The authors summarize some 13 parenteral routes through which materials are injected into the body. A nice section is presented on acute intramuscular irritation testing in the rabbit model as well as some alternatives. Intracutaneous irritation tests to evaluate tissue responses to extracts of materials are also covered. A brief discussion of the factors affecting irritation responses and test outcome is included. The reference listed for this chapter is extensive. However, the authors do not include any FDA guidance documents referring to recommended tests for medical devices.
Chapter 9—Immunotoxicology (ISO 10993-20)
Biocompatibility assessment is a critical part of the regulatory requirements for marketing applications. ISO 10993-20 provides the most relevant guidance along with FDA guidance documents. The authors provide a brief overview of the human immune system to stress the importance of proper testing. Several tables are provided that address cellular components, antibodies associated with immune responses, and mechanisms involved in cell-mediated cytotoxicity. A brief summary of the regulatory implications for medical device safety evaluation is provided with a focus on ISO 10993-20. The authors reference CDRH’s testing framework as published in draft and final guidance documents. This is very helpful to a reader who may not be fully aware of FDA’s position on this type of testing, since oftentimes the agency’s positon on a given ISO standard may vary in its application. A section on the historical evolution of testing is provided including reference to the modified Buehler procedure and information regarding its application. The authors present insightful information regarding different animal or rodent models for select tests. This information is also helpful to a reader who is interested in selecting robust tests for medical device evaluation. Once again, the reference list for this chapter is very good.
Chapter 10—Implantation Biology and Studies
In order to receive regulatory marketing approval or clearance from regulatory agencies, implantable medical devices and materials typically require extensive testing data. The authors provide a nice summary of the USP implantation test that is designed to evaluate relatively short-term exposures of primarily plastics and polymeric materials that are in direct contact with living tissue. A discussion of the microscopic examination of findings is provided as well as a review of different animal models that are routinely chosen. The focus of this chapter is on ISO 10993 (2007), part 6 that includes short-term and longer-term implant studies. Useful information relating to species selection and duration of implant periods by various species is given in easy-to-reference tables. Many of the laboratory control concepts common to the Good Laboratory Practices (GLP) regulations are infused into the discussion of these topics. The authors offer insightful information pertaining to controls and procedures for performing a variety of these tests. Some cross-referencing to Association for Standards and Testing of Materials (ASTM) standards for compatibility of biomaterials intended for surgical implants is also provided. A brief discussion regarding some problems with real-world interpretation of results is presented. The reference list for the chapter is very helpful for the reader who is seeking more detailed information on implant studies.
Chapter 11—Acute Systemic Toxicity Testing and Device Safety Evaluation
This is a relatively short chapter, but it provides a nice overview of the goal and purpose of acute systemic toxicity testing for medical devices. The FDA in particular is very interested in seeing teat data on systemic toxicity for medical device marketing applications since it helps provide a safety signal for the material implanted. Once again, the authors rely heavily on ISO 10993 and the USP for guidance on the content. A nice discussion of key factors to consider when performing this battery of tests, which include body weight number and size of dosage groups, is provided. The reader is cautioned about interpretation of specific toxicity screening data since the data are oftentimes continuous rather than occurring as a normal distribution. The chapter could have been strengthened if the authors had incorporated some of the FDA and other regulatory agency guidance documents into the discussion. The references for this chapter are good.
Chapter 12—Genotoxicity
The chapter on genotoxicity is perhaps one of the more complex topics in the entire book. The authors provide a very good introduction to why genotoxicity testing is important, and much of the information is presented in a format similar to flow of ISO 10993-3 and International Committee for Harmonization (ICH) guidance documents. A fairly in-depth discussion to DNA structure and the significance of gene mutations and chromosomal aberrations is included. The impact of genetic damage and the effect on the human gene pool are covered. The chapter contains multiple tables that summarize key concepts for the reader. The authors cover most of the more common tests and provide information regarding test preparation as well as analysis and interpretation of results. Unless the reader has an in-depth understanding of genotoxicity, the information provided may be somewhat difficult for the individual to apply in selecting and applying the appropriate tests for a given medical device. Perhaps, if the authors offered a few concrete examples of specific devices and the associated tests, then the reader may be able to better interpret the materials. The reference list provided for this chapter is extensive.
Chapter 13—Subchronic and Chronic Toxicity and Reproductive and Developmental Toxicity
The information presented in this chapter focuses on a group of studies that are intended to predict longer term effects that occur after continued or repeated exposure to an agent or material. This level of testing typically has been performed only in a few types of medical devices. The flow of this chapter is somewhat complex in that it covers many different topics including a brief introduction to GLP regulations and the Animal Welfare Act. A considerable amount of time is devoted to requirements for study designs and some common animal models. For medical device studies, it is a common practice to use a single species for testing subchronic and chronic biocompatibility. The authors provide summary tables to assist the reader to understanding key sections of the chapter. For example, histopathology is given a significant focus since it is generally considered to be the most significant part of data coming from these type studies. Several sections in this chapter have brief paragraphs about interpretation of data and therefore seem to make the flow of the material a little fragmented to the reader. Once again, an extensive reference list is provided for the chapter.
Chapter 14—Carcinogenicity
This chapter provides a very good overview of the tumorigenicity and carcinogenicity of devices and biomaterials with prolonged human exposure. Even though rarely required for most medical device marketing applications, these considerations are important for long-term implanted medical devices and materials. The ISO 10992-11 is typically the most commonly applied standard for medical devices marketed in the United States. Thus, the chapter is relatively short with the authors focusing on selection of animal models, dose selection, sample size, and other study design considerations. Once again, the authors provide some nice tables, which capture the key concepts presented in this section. A reference list is provided if the reader wishes to read more on the subject.
Chapter 15—Degradation Products and Impurities—Processes in Medical Devices
This is a very intriguing chapter in that the authors put forth evidence that potential degradation products from implanted medical devices and their components from either physical or chemical changes occur over time and that evaluation of these phenomena is important to understanding the safety profile of these devices. A brief review of metals and various potential degradation products is presented. Corrosion of metals when placed in contact with physiological tissues and fluids is well presented along with various corrosion testing schemes based on various ASTM standards. A discussion of ceramics and glass used in medical devices is provided with a focus on ISO 10993 where ware is a major concern for orthopedic implants. Polymer testing in accordance with ISO 10993-13 and resorbable polymer evaluation using a battery of in vivo and in vitro tests is provided. The risk of calcification is brought up in this chapter since it can occur with many bioprosthetic devices like heart valves. Leaching and migration risks of low-molecular-weight resins and phthalates are covered. Of special concern to medical devices is the effect of sterilization on the final products, and the authors devote several pages to reviewing the risks of various types of sterilization processes. A summary of sterility tests and their interpretations is provided. One weakness of the chapter is a lack of the authors referencing any of FDA’s guidance documents covering degradation products in medical devices. A brief section is presented on heavy metals. The reference list for this chapter is quite impressive.
Chapter 16—Special Device Cases
Up to this point in the book, the authors have presented a summary of tests applicable to medical devices consistent with ISO 10993. In this chapter, regulatory requirements for some broad categories of devices are summarized. The authors reference a variety of ASTM and USP tests in discussing these categories of devices. Respiratory and inhalation devices are covered with a brief summary of patient contact type risks. Summary tables are provided, which help the reader better select tests for use in evaluating these type devices. Ophthalmic devices including contact lenses and solutions and related tests are briefly addressed; however, no discussion of any regulatory agency guidance documents is included. The section on cardiovascular devices and prosthetic devices is included, but only a general description of the specific types such as catheters, guidewires, extracorporeal oxygenators, heart valves, and inferior vena cava filters is given with little new information regarding how these products should be tested. The authors provide in the introduction to this chapter a brief statement that regulatory agencies have issued some special guidance documents for testing these special groups of devices, but very little is included from these regulatory sources. The reader is left with only limited insight into how to select tests for these categories of special devices. The reference list for this chapter is much shorter but provides useful references to the reader.
Chapter 17—Combination Products
Based on the title of this book, a reader likely would expect to find new information about how combination products are reviewed and approved by FDA or regulatory agencies around the world. This is not the case. The role of FDA’s Office of Combination Products in rendering review designation of new products to specific centers is notably missing. The important role of the primary mode of action of the combination product by which FDA makes its decision for designating the lead review center is not addressed. The authors provide an interesting futuristic discussion of hypothetical trends for new combination products, and examples of existing device/drug combination are provided in a table for easy reference. The examples given in this chapter may be somewhat informative to the reader, but the process that a product developer must traverse in obtaining FDA approval for a combination product is not clearly described. Furthermore, there is no reference made to any FDA guidance documents addressing combination products and no information is given on how a company is to address Quality Systems Regulation (QSR) and Good Manufacturing Practices (GMP) requirements. Finally, the subject of testing combination products from a biomaterials perspective is missing so the reader is left to figure out how ISO 10993 applies to combination products. The reference list for this chapter is among the shortest of any in the book.
Chapter 18—Clinical Studies for Medical Devices
The authors provide a condensed historical summary of the evolution of medical device clinical studies. The increased trend for regulatory agencies to request clinical trial data is noted. A summary list of the most commonly found deficiencies in medical device submission is provided. The section on design considerations is good for anyone contemplating a clinical study involving a medical device. However, there is no reference to in vitro type studies, which is becoming a significant area of medical device development. References to many of the findings reported in the Temple Report are cited throughout this chapter, which stresses the importance of key elements. This chapter provides a nice platform of information for the reader to seek more specific input on study designs for a specific device. The authors do not include more recent guidance information from FDA regarding presubmission meetings and the potential value of these in refining clinical study research questions and protocol details. The FDA has issued several guidance documents on clinical study designs for medical devices including superiority and inferiority studies as well as using Bayesian analysis for medical device studies. The chapter does not include specific information on the statistical analysis plan requirements for medical device submissions. There is brief reference to Bioresearch Monitoring Program (BIMO) audits, but little trend information is included in this chapter, which may be of value to the reader. Notably missing from this chapter is the critical role of involving the lead investigators, biostatistician, clinical management, and regulatory personnel in planning the clinical study design, especially with a focus on developing measurable and meaningful clinical end points for assessing safety and effectiveness of the device. The reference list of this chapter includes many references relating to drug studies but few with direct reference to medical device trials. The location of this chapter within the book seems to be somewhat out of synch and might be better located following chapter 21.
Chapter 19—Leachable and Extractables From Medical Devices
This perhaps is one of the best chapters in the book. The authors provide an excellent introduction to the importance of assessing the safety of leachables and extractables in medical devices. A nice cross-reference discussion of ISO 10993 and related annexes with FDA guidelines is included, which aids the reader’s understanding of the subject matter, especially with an increased focus by regulatory agencies on the application of risk management and risk mitigation for medical products. A series of figure are included in the chapter, which help the reader quickly understand key points. The authors provide a nice overview of various tests and analyses available to researchers. Risk assessment is given considerable attention in this chapter, which is extremely important in the current regulatory environment. The chapter has a very good list of references.
Chapter 20—Toxicokinetics in Biomaterials and Device Safety Evaluation
The authors have done a good job of providing an overview of principles of toxicology and how these tests relate to the safety factor for biomaterials and devices. Tables are inserted, which provide the reader with fundamental terms common to pharmacokinetic studies as well as summary information on key concepts. The chapter provides a nice overview of common laboratory methods and includes important considerations relating to sampling methods of various body fluids. Considerations for biologically derived materials are also included in this chapter. The reference list is good.
Chapter 21—Special Studies
This chapter appears to be a “catch all” for topics and specific tests not previously covered in the text. In some sections, the information is quite general, and in others such as in the mouse embryo assay, the details relating to materials, study setup, and preparation and methods are in great detail. The section on Eye Irritation Study in Rabbits is quite short as are the other tests and methods presented in the text. The chapter does not have a summary so the reader is left his own to reach a conclusion as to how the information fits into the scheme for the text. The reference list is adequate and provides the reader with sources for additional information on the topics.
Chapter 22—Case Histories and Problem Resolution
The authors have chosen some major case studies associated with select medical devices or biomaterials. Phthalates leaching from polymer devices and bisphenol A are examples chosen to illustrate the potential issues associated with leachables. The authors summarize some of the FDA’s ongoing efforts to integrate data from product marketing application with literature and research information to better understand the risks involved. The example of powder being used as a type of lubricant on medical gloves and condoms is highlighted. In fact, FDA has just recently proposed a ban on marketing of powdered medical gloves. The example of latex allergies is also referenced, and a discussion of hypersensitivity is provided. Risks associated with silicones used in medical devices are presented. These examples set the stage for the second half of the chapter, which focuses on problem solving. This is an interesting approach that emphasizes the importance of risk assessment and monitoring of adverse events with marketed products. The authors provide a good conclusion to this chapter, which helps the reader better appreciate how the information fits into the entire theme of the book. This chapter has an extensive reference list.
Appendix A: Selected Regulatory and Toxicological Acronyms
The authors provide a long list of acronyms common to this field, which may be of significant value to individuals new to the area.
Appendix B: Contract Testing Laboratories
This appendix provide the names and contact information for many of the laboratories commonly providing testing services associated with evaluations of materials biocompatibility and finished medical devices.
Appendix C: Notable Regulatory Internet Addresses
The authors have provided a sample list of organizations and/or publications along with the type of product or services provided for easy reference including Internet address.
Appendix D: Non-US Medical Device Regulators
This appendix provides contact information only for regulators in Canada, United Kingdom, Japan, and Australia.
Appendix E. Definition of Terms and Lexicon of “Clinical” Observations in Nonclinical (Animal) Studies
This appendix provides a partial list of the most common terms associated with clinical observations in animal studies.
Summary
Biomaterials, Medical Devices, and Combination Products—Biocompatibility Testing and Safety Assessment is a well written and organized book covering the major topics associated with biocompatibility testing and safety testing of biomaterials used in medical devices. It provides the reader with basic information that one must understand when choosing tests for product evaluation, and the bibliography provided with each chapter is an excellent source for additional information on specific topics. The book could serve as a text for a college-level course or as a reference for professionals involved with R&D of medical products. As with any text book, the latest information available in many journals and guidance documents published by regulatory agencies is oftentimes not included in the book.
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