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The updated and expanded safety guide to all aspects of the drug development process
Drug Safety Evaluation, Second Edition presents an all-inclusive, practical guide for those who are responsible for ensuring the safety of drugs and biologics for patients, for health care providers, for those involved in the manufacture of medicinal products, and for all those who need to understand how the safety of these products is evaluated.
This Second Edition has been extensively revised and expanded to respond to the many changes in regulatory requirements as well as pharmaceutical and technological developments. Drawing upon more than twenty years of experience, author Shayne Gad explains the scientific and philosophical bases for evaluating specific concerns (e.g., cardiovascular safety, immunogenicity, carcinogenicity, development toxicity, etc.) to provide both understanding and guidance for approaching new problems.
Individual chapters address not only the general cases for safety evaluation of small and large molecules, but also all the significant major sub-cases: imaging agents, dermal and inhalation route drugs, vaccines, and gene-therapy products. Among the wide variety of topics covered are:
Acute toxicity testing in pharmaceutical safety evaluation
Safety assessment of inhalant drugs
Immunotoxicology in pharmaceutical development
Large animal studies
Evaluation of human tolerance and safety in clinical trials
More pertinent and practical than ever to the industry, Drug Safety Evaluation, Second Edition provides a road map for safety assessment as an integral part of the development of new drugs and therapeutics.
The preclinical assessment of the safety of potential new pharmaceuticals represents a special case of the general practice of toxicology (Gad, 1996, 2000; Meyer, 1989), possessing its own peculiarities and special considerations, and differing in several ways from the practice of toxicology in other fields-for some significant reasons. Because of the economics involved and the essential close interactions with other activities, (e.g., clinical trials, chemical process optimization, formulation development, regulatory reviews, etc.), the development and execution of a crisp, timely and flexible, yet scientifically sound, program is a prerequisite for success. The ultimate aim of preclinical assessment also makes it different. A good pharmaceutical safety assessment program seeks to efficiently and effectively move safe, potential therapeutic agents into, and support them through, the clinical evaluation, then to registration, and, finally, to market. This requires the quick identification of those agents that are not safe. At the same time, the very biological activity which makes a drug efficacious also acts to complicate the design and interpretation of safety studies.
Pharmaceuticals, unlike industrial chemicals, agricultural chemicals, and environmental agents,are intended to have human exposure and biological activity. And, unlike these materials and food additives, pharmaceuticals are intended to have biological effects on the people that receive them. Frequently, the interpretation of results and the formulation of decisions about the continued development and eventual use of a drug are based on an understanding of both the potential adverse effects of the agent (its safety) and its likely benefits, as well as the dose separation between these two (the "therapeutic index"). This makes a clear understanding of dose-response relationships critical, so that the actual risk/benefit ratio can be identified. It is also essential that the pharmacokinetics be understood and that "doses" (plasma tissue levels) at target organ sites be known (Scheuplein et al., 1990). Integral evaluation of pharmacokinetics are essential to any effective safety evaluation program.
The development and safety evaluation of pharmaceuticals have many aspects specified by regulatory agencies, and this has also tended to make the process more complex [until recently, as ICH (International Conference on Harmonization) has tended to take hold] as markets have truly become global. An extensive set of safety evaluations is absolutely required before a product is ever approved for market. Regulatory agencies have increasingly come to require not only the establishment of a "clean dose" in two species with adequate safety factors to cover potential differences between species, but also an elucidation of the mechanisms underlying such adverse effects as are seen at higher doses and are not well understood. These regulatory requirements are compelling for the pharmaceutical toxicologist (Traina, 1983; Smith, 1992). There is not, however, a set menu of what must be done. Rather, much (particularly in terms of the timing of testing) is open to professional judgment and is tailored for the specific agent involved and its therapeutic claim.
The discovery, development, and registration of a pharmaceutical is an immensely expensive operation, and represents a rather unique challenge (Zbinden, 1992). For every 9000 to 10,000 compounds specifically synthesized or isolated as potential therapeutics, one (on average) will actually reach the market. This process is illustrated diagrammatically in Figure 1.1. Each successive stage in the process is more expensive, making it of great interest to identify as early as possible those agents that are not likely to go the entire distance, allowing a concentration of effort on the compounds that have the highest probability of reaching the market. Compounds "drop out" of the process primarily for three reasons:
1. Toxicity or (lack of) tolerance.
2. (lack of) efficacy.
3. (lack of) bioavailability of the active moiety in man.
Early identification of poor or noncompetitive candidates in each of these three categories is thus extremely important (Fishlock, 1990), forming the basis for the use of screening in pharmaceutical discovery and development. How much and which resources to invest in screening, and each successive step in support of the development of a potential drug, are matters of strategy and phasing that are detailed in a later section of this chapter. In vitro methods are increasingly providing new tools for use in both early screening and the understanding of mechanisms of observed toxicity in preclinical and clinical studies (Gad, 1989b, 2001), particularly with the growing capabilities and influence of genomic and proteomic technologies. This is increasingly important as the societal concern over drug prices has grown (Littlehales, 1999). Additionally, the marketplace for new drugs is exceedingly competitive. The rewards for being either early (first or second) into the marketplace or achieving a significant therapeutic advantage are enormous in terms of eventual market share. Additionally, the first drug approved sets agency expectations for those drugs which follow. In mid-2001, there are 182 pharmaceutical products awaiting approval (41 of these are biotech products), the "oldest" having been in review seven years and some 1700 additional agents in the IND stage (Bryostowsi, 2001). Not all of these (particularly the oldest) will be economically successful.
The successful operation of a safety assessment program in the pharmaceutical industry requires that four different phases of the product-related operation be simultaneously supported. These four phases of pharmaceutical product support [discovery support, investigation new drug (IND) support, clinical and registration support, and product support] constitute the vast majority of what is done by the safety assessment groups in the pharmaceutical industry. The constant adjustment of balance of resources between these four areas is the greatest management challenge in pharmaceutical safety assessment. An additional area, occupational toxicology, is conducted in a manner similar to that for industrial environments and is the subject of Chapter 14 of this volume. In most companies, occupational toxicology is the responsibility of a separate group.
The usual way in which transition (or "flow") between the different phases is handled in safety assessment is to use a tiered testing approach. Each tier generates more specific data (and costs more to do so) and draws on the information generated in earlier tiers to refine the design of new studies. Different tiers are keyed to the support of successive decision points (go/no-go points) in the development process, with the intent of reducing risks as early as possible.
The first real critical decisions concerning the potential use of a compound in humans are the most difficult. They require an understanding of how well particular animal models work in predicting adverse effects in humans (usually very well, but there are notable lapses; for example, giving false positives and false negatives), and an understanding of what initial clinical trials are intended to do. Though an approved IND grants one entry into limited evaluations of drug effects in man, flexibility in the execution and analysis of these studies offers a significant opportunity to also investigate efficacy (O'Grady and Linet, 1990).
Once past the discovery and initial development stages, the safety assessment aspects of the process become extremely tightly connected with the other aspects of the development of a compound, particularly the clinical aspects. These interconnections are coordinated by project management systems. At many times during the early years of the development process, safety assessment constitutes the rate-limiting step; it is, in the language of project management, on the critical path.
Another way in which pharmaceutical safety assessment varies from toxicology as practiced in other industries is that it is a much more multidisciplinary and integrated process. This particularly stands out in the incorporation of the evaluation of ADME (absorption, distribution, metabolism and excretion) aspects in the safety evaluation process. These pharmacokinetic-metabolism (PKM) aspects are evaluated for each of the animal model species (most commonly the rat and dog or primate) utilized to evaluate the preclinical systemic toxicity of a potential drug prior to evaluation in man. Frequently, in vitro characterizations of metabolism for model (or potential model) species and man are performed to allow optimal model selection and understanding of findings. This allows for an early appreciation of both the potential bioavailability of active drug moieties and the relative predictive values of the various animal models. Such data early on are also very useful (in fact, sometimes essential) in setting dose levels for later animal studies and in projecting safe dose levels for clinical use. Unlike most other areas of industrial toxicology, one is not limited to extrapolating the relationships between administered dose and systemic effects. Rather, one has significant information on systemic levels of the therapeutic moiety; typically, total area under the curve (AUC), peak plasma levels ([C.sub.max]), and plasma half-lives, at a minimum. Chapter 18 looks at these aspects in detail.
The state of the art for preclinical safety assessment has now developed to the point where the resulting products of the effort (reports, IND/NDA summaries, and the overall professional assessment of them) are expected to reflect and integrate the best effort of all the available scientific disciplines. Actual data and discussion should thus come from toxicology, pharmacology, pathology, and metabolism, at a minimum. The success of current premarket efforts to develop and ensure that only safe drugs make it to market are generally good, but clearly not perfect. This is reflected in popular (Arnst, 1998; Raeburn, 1999) and professional (Moore, et al., 1998; Lazarou et al., 1998) articles looking at both the number of recent marketed drug withdrawals for safety (summarized in Table 1.1) and at rates of drug-related adverse drug events and deaths in hospital patients. It is hoped that this system can be improved, and there are a lot of efforts to improve or optimize drug candidate selection and development (Lesko, et al., 2000).
1.2. REGULATORY REQUIREMENTS
Minimum standards and requirements for safety assessment of new pharmaceuticals are established by the need to meet regulatory requirements for developing, and eventually gaining approval to market, the agent. Determining what these requirements are is complicated by (1) the need to compete in a global market, which means gaining regulatory approval in multiple countries that do not have the same standards or requirements, and (2) the fact that the requirements are documented as guidelines, the interpretation of which is subject to change as experience alters judgments. The ICH process has much improved this situation, as detailed in Chapter 2.
Standards for the performance of studies (which is one part of regulatory requirements) have as their most important component good laboratory practices (GLPs). Good laboratory practices largely dictate the logistics of safety assessment: training, adherence to other regulations (such as those governing the requirements for animal care), and (most of all) the documentation and record-keeping that are involved in the process. There are multiple sets of GLP regulations (in the United States alone, agencies such as the FDA and EPA each have their own) that are not identical; however, adherence to U.S. Food and Drug Administration GLPs (FDA, 1987a) will rarely lead one astray.
Not all studies that are done to assess the preclinical safety of a new pharmaceutical need be done in strict adherence to GLPs. Those studies that are "meant to support the safety of a new agent" (i.e., are required by regulatory guidelines) must be so conducted or run a significant risk of rejection. However, there are also many other studies of an exploratory nature (such as range finders and studies done to understand the mechanisms of toxicity) that are not required by the FDA, and which may be done without strict adherence to GLPs. A common example are those studies performed early on to support research in selecting candidate agents. Such studies do not meet the requirements for having a validated analytical method to verify the identity, composition, and stability of materials being assayed, yet they are essential to the processes of discovery and development of new drugs. All such studies must eventually be reported to the FDA if an IND application is filed, but the FDA does not in practice "reject" such studies (and therefore the IND) because they are "non-GLP."
There is a second set of "standards" of study conduct that are less well defined. These are "generally accepted practice," and though not written down in regulation, are just as important as GLPs for studies to be accepted by the FDA and the scientific community. These standards, which are set by what is generally accepted as good science by the scientific community, include techniques, instruments utilized, and interpretation of results. Most of the chapters in this book will reflect these generally accepted practices in one form or another.
Guidelines establish which studies must be done for each step in the process of development. Though guidelines supposedly are suggestion (and not requirements), they are in fact generally treated as minimums by the promulgating agency. The exceptions to this are special cases where a drug is to meet some significant need (a life-threatening disease such as AIDS) or where there are real technological limitations as to what can be done (as with many of the new biologically derived [or biotechnology] agents, where limitations on compound availability and biological responses make traditional approaches inappropriate).
There are some significant differences in guideline requirements between the major countries [see Alder and Zbinden (1988) for an excellent country-by-country review of requirements], though this source is now becoming dated. The core of what studies are generally done are those studies conducted to meet U.S. FDA requirements. These are presented in Table 1.2. As will be discussed in Chapter 2, these guidelines are giving way to the ICH guidelines. However, while the length and details of studies have changed, the nature and order of studies remain the same.
The major variations in requirements for other countries still tend to be in the area of special studies.
Excerpted from Drug Safety Evaluation by Shayne C. Gad Excerpted by permission.
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|About the Author|
|Ch. 1||Strategy and Phasing for Drug Safety Evaluation in the Discovery and Development of Pharmaceuticals||1|
|Ch. 2||Regulation of Human Pharmaceutical Safety||30|
|Ch. 3||Information Sources: Building and Maintaining Data Files||99|
|Ch. 4||Screens in Safety and Hazard Assessment||112|
|Ch. 5||Acute Toxicity Testing in Drug Safety Evaluation||130|
|Ch. 7||Subchronic and Chronic Toxicity Studies||237|
|Ch. 8||Developmental and Reproductive Toxicity Testing||258|
|Ch. 9||Carcinogenicity Studies||297|
|Ch. 10||Safety Assessment of Inhalant Drugs||335|
|Ch. 11||Irritation and Local Tissue Tolerance in Pharmaceutical Safety Assessment||367|
|Ch. 12||Special Concerns for the Preclinical Evaluation of Biotechnology Products||404|
|Ch. 13||Formulations, Routes, and Dosage Designs||442|
|Ch. 14||Occupational Toxicology in the Pharmaceutical Industry||505|
|Ch. 15||Immunotoxicology in Pharmaceutical Development||527|
|Ch. 16||Large Animal Studies||595|
|Ch. 17||The Application of In Vitro Techniques in Drug Safety Assessment||634|
|Ch. 18||Pharmacokinetics and Toxicokinetics in Drug Safety Evaluation||691|
|Ch. 19||Safety Pharmacology||737|
|Ch. 20||Evaluation of Human Tolerance and Safety in Clinical Trials: Phase I and Beyond||764|
|Ch. 21||Postmarketing Safety Evaluation: Monitoring, Assessing, and Reporting of Adverse Drug Responses (ADRs)||831|
|Ch. 22||Statistics in Pharmaceutical Safety Assessment||862|
|App. A||Selected Regulatory and Toxicological Acronyms||971|
|App. B||Definition of Terms and Lexicon of Clinical Observations in Nonclinical (Animal) Studies||975|
|App. C||Notable Regulatory Internet Addresses||979|
|App. D||Glossary of Terms Used in the Clinical Evaluation of Therapeutic Agents||990|