Abstract
Advanced Issue Resolution in Safety Pharmacology is a welcome addition to reference information on the application of safety pharmacology approaches in drug development.
The intent is clearly stated in the Introduction which is “to foster a discussion of more advanced topics in safety pharmacology, data collection and the application of those data for clinical translation.” The editors, Mary Jeanne Kallman and Michael J. Pugsley, are veterans of this scientific discipline and past presidents of the Safety Pharmacology Society serving in 2011 and 2015, respectively. They are highly respected as advocates of the topic of safety pharmacology and, in this book, continue to contribute to disseminating an understanding of its potential for improving drug safety profiles as a result of a broader, systematic application of safety pharmacology principles to drug development. Dr. Kallman has insights gained from working in big pharma and the contract research organization (CRO) world. Now as a consultant, she continues to advise on central nervous system (CNS) and drug abuse liabilities and frequently publishes and presents on these topics. Dr. Pugsley has spent most of his career working in big pharma and also in the biotech space. Responsibilities have included conduct of early in vitro and in vivo Discovery, IND-enabling Toxicology and core Safety Pharmacology studies for multiple therapeutic areas for both small molecules and biologicals. He recently published the book entitled “Principles of Safety Pharmacology,” has authored multiple reviews, published numerous scientific articles on safety pharmacology, and serves on the editorial board of several pharmacology journals.
As is commonly done with a textbook of this nature, multiple authors have contributed to the chapters that are reflective of their specific areas of expertise and their overall appreciation of the complexities of the subject of safety pharmacology. Backgrounds of the 26 contributors’ are predominantly from large pharmaceutical companies based primarily in the United States and a few from Europe. Perspectives of some contributors may also be influenced by experience as consultants or that gained while in a CRO and in one instance at the US Food and Drug Administration (FDA). As such, the styles are eclectic and variable in quality, length, and points of emphasis. Some are focused on a specific area, others attempt to address entire organ systems within a very short space and yet others are general overviews.
There are 338 pages of content distributed among 15 chapters that roughly follow a similar structure as follows. First, the reader is stepped through the basics of topic of the chapter to provide a foundational understanding, which is then expanded upon with respect to adverse consequences and information on pharmacological classes that are known to have these effects. Subsequently, approaches to resolution and understanding of the issue(s) are addressed, including methodologies and models, as well as proposed strategies. Finally, case studies illustrate how the use of these advanced concepts have played a significant role in go/no-go decision-making, plans for backup identification, and how pharmacokinetic/pharmacodynamic (PK/PD) modeling is valuable in building risk-benefit profiles.
The short 6-page introductory chapter, Introduction to Issue Resolution, is provocative more than detailed and, of course, is mainly focused on summarizing what is to come. The chapter quickly acknowledges the regulatory drivers of safety pharmacology and that the focus has primarily been on the 3 core components of functional safety testing: cardiovascular, CNS, and respiratory, and moves on to note that the practice of safety pharmacology has given less attention to “secondary” systems. Although the core systems approach has been useful, there is a view that the guidance documents have a degree fostered more of a box-checking exercise by naming these other systems as supplementary as well as the idea that even for core systems only certain aspects of evaluation are really necessary. This book, along with other publications that are extensively referenced, goes some way to correcting that perception. These supplemental studies may be secondary from the point of view of acute safety but overall derangements of other organ systems, such as renal, gastrointestinal (GI), and immune function, are nevertheless a notable cause of drug approval failures. Clearly, a situation to be addressed in view of the current estimate of $1 to $1.8 billion cost and often over a decade to get to the approval stage. Thus, while a primary focus is to identify more advanced alternatives for not only understanding preclinical effects to guide early screening efforts and first in human (FIH) safety, there is also promise of their predictive value in the clinic in later stages of development. Another point worth noting is that the chapters provide a useful compendium of some of the advanced methods available. This is also a guide to creating safety assessment strategies and data that can aid in decision-making. Documentation of how a vision for resolution strategies can be built is useful for those within the drug development space. For teaching purposes, information on this aspect of pharmacology, including industry expectations, is commonly given short shrift in basic science departments. Thus, the book will be useful in preparing students not only for a career in academia, which is focused on mechanistic understanding and discovery of novel drug targets, but also for considerations that are important to industry, such as clinical implications and portfolio management. In the later parts of the chapter, some interesting newer FDA information is summarized. The number of drugs approved annually, failure rates, and evidence of new trends is discussed. A significant number of recent new drug approvals are for breakthrough therapies and first in class drugs. As such, the point is made that this may result in further need to find new techniques and approaches for issue resolution in safety pharmacology. As noted, the literature or previous wisdom may not apply. The need for predictive biomarkers that coincide with whole animal study end points and better still that have clinical translatability is also emphasized. For certain areas of safety, there are failures all the way through the development path, such as with cardiovascular even with all the attention that this aspect of safety pharmacology has received for the past couple of decades. The chapter ends with a summary of areas and stages of drug attrition, particularly CNS, the importance of considering the sensitivity of the target population to side effects, such as the elderly or those on multiple drugs. Emphasis on issues that arise later in drug development, as well as on approaches that are of value across the entire safety assessment continuum, such as PK/PD modelling and imaging technologies, and guidance on when to implement these more advanced techniques and clinical translation.
Chapter 2 on Selection of Nontraditional Species for Issue Resolution Studies, which at 33 pages is one of the longest sections in the book. It begins with an introduction to the International Conference on Harmonization guidelines S7A and S7B 1,2 covering safety pharmacology, and also S6(R1) 3 for biotechnology derived molecules, its purpose, and the general acceptance of the rat, dog, and nonhuman primate as the most commonly used test species as well as summarizing nontraditional species. As per the title of this chapter, considerations for species selection for the core battery are discussed separately and in-depth alongside the specific types of tests and comparative validation of newer technologies, tier 1 and tier 2 testing, drug effects, and data interpretation. For example, 9 pages cover CNS methodologies and concepts beginning with the basic Irwin/functional observation battery screening. This is followed by sections on follow-up issue resolution assessment with respect to abuse liability testing as defined in the recent guidance documents from European Medicines Agency, 2006 4 , and FDA 5 , 2017, learning and memory, startle response, seizure liability, and sleep disorders which are all covered again with different emphasis in later chapters. The other 2 core systems, cardiovascular and respiratory, are covered with a bit more brevity, but the essentials are presented. I was also glad to see at least some detail on renal and GI supplemental studies. Indeed, this is the only place where renal is covered including information on biomarkers. Besides the other species options, there is some discussion of the reasons for using these nontraditional species and some coverage of advantages and disadvantages as well as cross laboratory validations in some instances which will continue to evolve and which could be elaborated upon further in future editions. This is an extensive area to address, and this kind of comparative data is not always readily available. To have all this information in a single chapter is useful and is supported by an extensive 7-page reference section.
For those of us more capable of appreciating biology rather than mathematics, the consideration of modeling may make one’s brain go numb. Not so in Chapter 3 on The Use of Modeling to Facilitate Decision-Making in Safety Pharmacology Assessments which is so very readable and begins with an appealing paragraph that makes a readily absorbable case for the importance of this topic and how it can also be applied during clinical development. Data generated in the conduct of safety pharmacology studies are so amenable to the use of modeling for predicting drug safety in man based on PK/PD data generated in animal models. The chapter provides a very helpful introduction to basic concepts such as the meaning of top-down, bottom-up (systems biology), middle-out (quantitative systems pharmacology), and semi-mechanistic models. It steps one through increasing levels of complexity having established the very basics and links these concepts clearly to the utility that they provide, with examples. Anyone reading this chapter will come away with a good understanding and appreciation of the value and applicability of modeling not only to safety pharmacology but also to drug development in general.
Chapter 4 on Issue Resolution of Drug-Induced Breathing Instability and the Occurrence of Apneic Events defines the measurement of breathing instability, mechanisms, and animal models and how much the subject has evolved with the recognition of both the need to treat this disorder associated acute and chronic clinical risk and that it can arise as a drug side effect. A strategy for identifying drug candidates that may cause breathing instability and one case study are also included.
Gastrointestinal side effects in drug development are common and a limitation in drug testing where there is either emesis or diarrhea which can subsequently affect PK and other functional indices such as cardiovascular end points. Gastrointestinal side effects of drugs are ranked as the top adverse effect in humans. While not life-threatening, they certainly impact patient compliance and quality of life, and therefore, Chapter 5 – The Impact of Drug-Induced Effects on the Gastrointestinal System: Challenges and Issue Resolution for Safety Pharmacology is certainly an important topic and too often overlooked. This chapter describes early screening methods and provides a detailed account of common end points, assays, model systems, direct and indirect effects of drugs, and mitigation strategies concluding a final section on future directions.
There is a heavy emphasis on the CNS, with 6 of the 15 chapters presenting various facets of the practice of evaluating this core discipline. All of these chapters have extensive reference sections, so again a most useful summation of the various topics covered with plenty of additional resources provided. There is also an evolving recognition of the need for an improved understanding of abuse and dependence liability and prevention of the significant rates of failure of drugs because of other undesirable CNS side effects. Besides the importance of the CNS in behavior, other chapters also touch on the influence of CNS in regulation of major organ systems and resetting of reflexes such as in the pathophysiology of respiratory apnea and autonomic influences on cardiovascular homeostasis. Clearly, a closer examination of CNS effects in drug failures is timely. Chapters 6 to 11 cover Sleep and Sleep Disruption; Self-Injurious Behavior in Clinical and Preclinical Populations: Description, Etiology, and Management; Approaches for Early Identification of Abuse Potential Liability; Issue Resolution of Motor Deficits and Stereotypies; and Utility of Progressive Ratio Schedules of Reinforcement in Abuse Potential Assessments.
The chapter on the subject of sleep describes sleep stages, the impact of age, disease states, methods of measurement such as electroencephalography (EEG), sleep disturbance and models thereof, results of deprivation on things such as obesity, diabetes, and the cardiovascular system, as well as mood and reasons, with examples, as to why this should be evaluated, how to do so, and how this subject readily translates to human.
Animals do not appear to exhibit suicidal behavior, but they do exhibit impulsive, compulsive, stereotypic, and major self-injurious behavior (SIB) spontaneously, and this can be translated to human behavior in terms of the same precipitating social factors that apply. Several neurotransmitter systems have been implicated in either the production or maintenance, and as such, SIB can be induced by certain drug classes especially after repeated administration. The major drug classes and animal studies that address mitigation of this behavior are discussed.
Drug abuse liability has become a huge issue globally. Reviews, strategies, and very recent guidance for industry describing tests to characterize abuse potential for drug classes with probable risk and for those with unknown potential are discussed. Integration of the various approaches for proactive screening and more sophisticated testing and several examples of successful strategies for abuse liability resolution are presented.
A considerable effort is devoted to defining normal and disturbed straightforward motor control mechanisms versus definition of adaptive and maladaptive stereotypies and the 3 factors that determine the nature of stereotypical behaviors. Behaviors of rats and nonhuman primates are presented in extensive tables as well as approaches to preclinical screening and a discussion of neurological pathways involved with reference to drug effects. The use of behavioral assessments and factors that may confound interpretation is addressed. Finally, a case example is presented.
Convulsions and seizures as separate manifestations that may occur in parallel in response to adverse CNS effects are qualified, and methods, challenges, and factors that influence susceptibility are put into the context of the management of a risk assessment and safety margins.
Since its introduction in the 1940s, the self-administration assay for assessment of abuse potential and drug-seeking behavior has become more and more refined. Chapter 11 on the Utility of Progressive Ratio Schedules of Reinforcement in Abuse Potential Assessments describes the conduct and applicability of the basic method of fixed-ratio schedule reinforcement and elaborates further on the more involved progressive-ratio model in depth. Test subject considerations, gender differences, selection of training drugs, and other aspects of study design are highlighted. The utility of the progressive-ratio model for assessing anhedonia during physical dependence and withdrawal is also covered.
Although Imaging in the Resolution of Safety Pharmacology Issues is not routine, Chapter 12 certainly makes a case for their value, in particular their translatability to the clinic. A very useful description of the various imaging techniques with their advantages and limitations is followed by 6 case studies. An appreciation of the clinical relevance and value for mechanistic understanding through these unique end points is useful on a selective basis in safety pharmacology.
Cardiovascular Safety Pharmacology Issue Resolution (Chapter 13) has been and continues to be the most widely covered since the inception of safety pharmacology as a specific discipline and not surprisingly given the number of drugs that fail at each stage of development due to adverse cardiovascular effects. Progress continues to be made in the different types of safety pharmacology cardiovascular studies that address not only arrhythmogenic liabilities but also blood vessels, blood constituents, as well as the key role of the nervous and renal systems. The chapter does not elaborate or provide references to these finer nuances, such as restitution analysis, that is, the quantification of the ability of the heart to recover from one beat to another as index of cardiac stress, advances made as a result of the comprehensive in vitro proarrhythmia assay initiative, even if it is addressed in other texts but about which researchers in other areas of drug safety assessment reading this book may have less knowledge. It does, however, present 4 instructive case studies that show how the application of issue resolution enabled drugs to continue in development with the appropriate cardiovascular monitoring, design-out cardiac liabilities, and make dose adjustments with an understanding of the cardiovascular safety issues.
Chapter 14 – Use of In Vitro Models in Drug Development and Issue Resolution – includes an in-depth discussion of the use of in vitro pharmacological profiling assays that target receptors, enzymes, and ion channels and subsequent verification using concentration response curves and/or functional assays to establish agonist or antagonist activity. A suggested panel of 44 targets is reviewed very early in compound selection, and for the most promising candidates, the number is expanded to a recommended list of 70 targets. Follow-up assays are then conducted depending on the initial results such as high-throughput electrophysiology screening. These in vitro assays have usage in selecting molecules with optimal safety margins for the target versus off-target activity of which detailed examples are provided. Classical bioassay approaches using isolated tissues that still have some utility or other in vitro screening approaches are not described.
The final chapter on Future Needs in Issue Resolution of Problems That Arise in Drug Development considerably expands on the issues initially mentioned in the Introduction, summarizing reasons for drug attrition and includes specific data and reference sources. Current common practices in safety pharmacology such as the trend to just conduct core battery studies or interest in a fit-for-purpose approach supported by models that are validated, robust, and provide reliable data that lend itself to predictivity in the clinic are covered. Chapter 15 also addresses, recent advances in safety pharmacology, the usefulness of risk assessment schemata and the limitations, as evidenced by the description of 2 examples of serious adverse events in the clinic in FIH trials, and the importance of continuing to develop predictive models as well as a consideration of the integration of functional end points in repeat dose toxicology studies which is becoming more common, especially with biologicals. The inclusion of a brief historical perspective is both informative and inspiring, and the summary of standard and novel safety pharmacology methods along with recent references – 6 pages in all – provides a good resource for further study. Finally, 3 additional case studies further illustrate the utility of safety pharmacology in drug development.
In some chapters, the focus is not entirely clear and there is difficulty in following the thread of the subject matter and applied relevance in the practice of safety pharmacology either with respect to moving a drug candidate to market or as a tool in de-risking decision-making. It is a heavy burden to expect the editors to provide intensive content and grammatical oversight, and the book would have benefitted from more input from a medical copywriter/proof reader on the part of the publisher for consistency. Similarly, the quality of the figures and tables is also variable with some being difficult to read because of poor use of spacing and small font. Illegibility in some instances could have been corrected by horizontal placement, use of a bolder font color, or less dense background. Additionally, legends do not provide a sufficient explanation of the information such that it is unclear how the data presented is derived without reference to the original source. There are also instances where the figures are poorly placed with respect to the actual text. Provision of references is extensive and many of them are very recent. However, use of http links instead of full references will only be useful as long as these remain up to date.
More information on conduct of an integrated approach combining toxicology and safety pharmacology end points within the same study would have been useful and a chapter that addresses the potential for safety pharmacology in disease models or to model specific target populations such as pediatrics or in the elderly or functional drug interactions would be of interest. Perhaps these points and the potential utility and challenges associated with the use of disease models in safety pharmacology will be covered in later editions.
In summary, the text underscores how knowledge of advanced issues in safety pharmacology can be applied – with examples – to the selection of drug candidates at the interface of Discovery and Early Drug Development. It also covers how these data can be incorporated into the package of pharmacological information that provide assurances of drug safety prior to FIH studies, and subsequently, how it can be used to explore and understand possible mechanisms of adverse events in the course of Clinical Development. At each stage, these insights can then inform the intelligent design of even safer drugs with fewer undesirable side effects while retaining therapeutic effectiveness and creating an appropriate risk–benefit profile. At the approval stage, it is all about clinical, understandably. It has always been my position that “when it comes to gaining final regulatory approval that nonclinical is really not that important in the overall scheme of things – until it is!” Then, the application of safety pharmacology, especially advanced safety pharmacology, can go a very long way to mitigating the concerns about safety in the clinic, can make all the difference in determinations as to whether an adverse effect is a real clinical safety risk, aid in the rational selection of biomarkers, and can influence the decisions as to whether the molecule can be granted approval to market. Besides providing a useful resource that compiles a lot of different aspects of safety pharmacology, this advanced textbook also leaves one with more food for thought, excitement about the promise of safety pharmacology and how it continues to grow and evolve far beyond the core battery of studies. This book will be a useful resource for any individual interested in safety aspects of drug discovery and development from discovery to the clinic, regulatory approval to postmarketing and academics (including graduate students and postdoctoral fellows) in medical sciences.