Abstract
More than 1000 pages of thoughtful and informative guidance for developing human and veterinary medicines derived from biologic sources lies sandwiched between a 7-page foreword, coauthored by the editor and one of her contributors, and the afterword. The book also contains a 30-page index that is followed by 8 pages of color plates. The final chapter, written by the editor’s coauthor of the foreword, provides a continuity and overview often lacking in similar comprehensive texts. The book expresses a major theme throughout the text: safety assessment of biopharmaceuticals is an exercise that, by the very nature of biopharmaceuticals, must be carried out on a case-by-case approach. The foundation of this all-important concept is laid early in the book (Chapter 3: “The Principles of ICH S6 and the Case-by-Case Approach”). This chapter, written by the editor, initiates the case-by-case theme that permeates throughout the remainder of the book in subsequent chapters, written by almost 70 contributors.
Parallel concepts running through the text reinforce the case-by-case theme. Contributors to many of the chapters compare, for reference purposes, the process and methods used for safety evaluation of small-molecule drugs to those processes and methods that have been or could be used for biopharmaceuticals. In effect, the process of comparing a biopharmaceutical to small-molecule drugs results in a de facto case-by-case evaluation for the biopharmaceutical. Furthermore, the book is replete with examples that adverse reactions to biopharmaceuticals are, to a large extent, rooted in adverse pharmacology of the specific biopharmaceutical. Because pharmacology is individualized for each biotherapeutic agent, the case-by-case approach for safety evaluation emerges as the approach of choice for evaluating the safety of biopharmaceuticals. The editor and her contributors support the case-by-case theme not only in theory but also with evidence.
Many disciplines contribute to the swift and effective development of biopharmaceuticals, and the need for successfully developed biopharmaceuticals is driven by the expectations of society. These expectations are specifically focused in the patients who seek cures, physicians searching for tools they can use to treat their patients, and investors who financially support the journey. The editor and her various contributors make a convincing case that their principle theme of case-by-case safety assessment, supported by experiences of small-molecule drug safety assessment, is the most efficient way to achieve the common goal of biopharmaceutical development for all of the stakeholders.
The principles and concepts presented in the book are written from the perspective of biopharmaceutical research, development, and evaluation and are useful to academic and industry research scientists. The material presented in the book is also valuable to regulatory agency personnel, clinical investigators, ethics committees, consultants to the biopharmaceutical industry, and venture capitalists. This breadth of applicability is derived in the book’s comprehensive accounts of the past 20 years in biopharmaceutical preclinical development experiences and practices. The historical perspective gives meaning to the many developmental steps and processes for those not actively involved in preclinical biopharmaceutical development such as regulatory agencies, ethics committees, and venture capitalists. Clinical investigators will find the text useful by providing a framework in assessing individual biopharmaceuticals for which they are preparing to take into the clinic for the first time. However, the unsurpassed value of the book is the value to those scientists who are intimately involved in preclinical development such as target identification, lead candidate selection, pharmacokinetic/toxicokinetics, and pharmacology/pharmacodynamics. The scientist who is actively engaged in biotherapeutics development will greatly appreciate this guidance for applying the case-by-case approach for evaluating the safety of biopharmaceuticals.
Part I, which lays the foundation for the remainder of the text, has 2 chapters with a total of 41 pages. The first chapter of Part I sets forth the definitions and regulations covering biopharmaceuticals. The second chapter addresses biopharmaceutical production issues and describes the methods and guidelines for the production of acceptable recombinant proteins. In addition, the chapter lists environmental assessment requirements for manufactured recombinant proteins. The final third of the second chapter addresses the key elements that should be considered with a production system that may have been changed.
“The Principles of Preclinical Development,” which is the title of Part II, has 4 chapters dedicated to the International Conference of Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, specifically ICH S6. Just as the chapters in Part I set the stage for the entire book, the first chapter in Part II sets the stage for this part and, indeed, the theme of the book.
The first chapter in Part II, titled “The Principles of ICH S6 and the Case-by-Case Approach,” is the keynote of the book and lays the foundation for the book’s major theme. This chapter gives a history of the regulatory framework and discusses how ICH S6 can or should be implemented. Of particular note, Table 3-2 outlines the comparison of the safety evaluation process for small-molecule pharmaceuticals to biopharmaceuticals, which sets the stage for the subordinate, but supporting nonetheless, concept expressed in the book. This comparison, although valuable to the practicing toxicologist, other nontoxicologists associated with a biopharmaceutical development will find this 2-page comparison extremely important. Other topics included in this chapter, which constitute the backbone for a toxicity testing scheme for biopharmaceuticals, include the following: use of animal models for toxicity testing, selection of relevant species, cross-reactivity, use of analogous products, use of relevant test systems, and dose (selection, schedule, duration, and response). The other 3 chapters of Part II describe the implementation of ICH S6 for the European Union, Japanese, and US perspectives.
Part III contains approximately 75 pages, divided between 2 chapters covering (1) the comparison of preclinical developments between small molecules and biopharmaceuticals and (2) comparability of a licensed product after a manufacturing change. Just as the first chapter of Part II laid the foundation for the major theme of a case-by-case approach for safety evaluation for biopharmaceuticals, the first chapter of Part III lays the foundation for comparing the safety evaluation approaches for small-molecule therapeutics to those that are derived from biologic sources.
Part IV contains approximately 125 pages distributed among 5 chapters. The focus of Part IV is centered on selecting the appropriate animal species for the preclinical assessment of biopharmaceuticals from various perspectives such as pharmacokinetics, pharmacodynamics, and animal models. Any toxicologist would readily agree that for a safety assessment process, whether it be for therapeutic agents or for nontherapeutics, surrogate testing may be necessary. For the surrogate to provide meaningful information for assessing safety for the target or intended species, adequate similarity must exist between the surrogate and the target. Part IV addresses this requirement for biopharmaceuticals. Perhaps the titles of Chapter 10 and 11 could have been selected to better reflect the requirement of similar immune physiology between the surrogate and target, but the fact remains that these 2 chapters do address the requirement for a similar immune physiology when evaluating the safety of biopharmaceuticals.
Part V is the necessary complement to Part IV. This part, consisting of 8 chapters and covering 183 pages, covers the main topics that speak to the part’s title: “Safety/Toxicity Endpoints.” The endpoints specifically discussed in Part V include safety pharmacology, genetic toxicology, general toxicity testing, immunotoxicology, reproductive toxicity, and carcinogenic risks. Because immunological responses are important considerations in biologically derived products, various perspectives are covered such as general immune system toxicity, immunomodulation, hypersensitivity, and autoimmunity. Immunophysiology is addressed throughout Part V in all of the chapters. The biochemistry and additional immunophysiology are also addressed in Chapters 10 and 11 of Part IV. Perhaps a flaw in Part V, albeit ever so minor, is the lack of reference to Chapters 10 and 11 of Part IV. However, with a minimal effort, a complete immunological assessment of a biopharmaceutical can be achieved by reviewing selected chapters in 2 parts.
Part VI (“Specific Considerations Based on Product Class”) is the cornerstone of the book. This part has approximately 315 pages distributed among 14 chapters (Chapters 22-35). Clearly, this part is an exercise of learning from the past and what safety assessment issues are likely to appear for biopharmaceuticals developed in the future. This part strikingly demonstrates the major theme of the book: caseby-case safety evaluation.
Chapter 22 describes, as its title states, “Current Practices in the Preclinical Safety Assessment of Peptides.” The outline of the chapter, identified in the first section of the chapter as Contents, is a road map for issues that the toxicologist should address when considering the safety not only of peptides but also of all biopharmaceuticals. To some extent, peptides bridge small-molecule therapeutics and large, complex biopharmaceutical molecules. Consequently, the author smoothly describes the transition of safety evaluation from small-molecule, new chemical entities to large, complex biopharmaceuticals using peptides as the bridge.
Other product classes of biopharmaceuticals described in Part VI include enzymes, oligonucleotides, oncology drugs, monoclonal antibodies, immunomodulatory biopharmaceuticals, protein scaffolds, immunotoxins, blood products, viral vaccines, gene therapy biopharmaceuticals, cell-based therapies, biopharmaceutical/device combination therapies, and tissue-engineered products (neo-organs).
Part VII (“Preclinical Study Design, Implementation and Analysis”) and Part VIII (“Transitioning From Preclinical Development to Clinical Trials”) provide the basis of a working plan for developing a preclinical safety evaluation plan for a biopharmaceutical. The 4 chapters in Part VII address both generic preclinical safety assessment issues as well as those specific to biopharmaceuticals. The single chapter in Part VIII emphasizes the need for a rational approach for selecting the first-in-human dose. The chapter contains 3 working examples illustrating how to effectively use developing scientific data for 3 types of biopharmaceuticals in the context of the judgments that are required.
Part IX, which is titled “Afterword,” is the overview of the book’s purpose. The brief but powerful chapter covers, in a little over 10 pages, what a biopharmaceutical is, how history can assist in developing a preclinical safety assessment program, and the fundamental questions associated with preclinical testing of biopharmaceuticals.
The editor and her coauthor of the foreword state that the goal of the book “is to provide a comprehensive reference book for the preclinical discovery and development scientist whose responsibilities span target identification, lead candidate selection, pharmacokinetics, pharmacology and toxicology and for the regulatory scientist whose responsibilities include the evaluation of novel therapies.” The book not only achieved that goal in the broadest sense, but each contributor of the individual chapters that are part of the book also stayed on course and reflected the book’s goal. With the exception of shifts in topical matter, there is a seamless transition among the chapters for presenting the book’s theme of case-by-case evaluations for biopharmaceuticals.
The types of biomolecules requiring a preclinical safety evaluation for human and veterinary medicine are limited only by therapeutic imagination. The potential for new biopharmaceuticals and new applications of biologically derived molecules appears to be open-ended. For the toxicologists and clinical investigators charged with the responsibility of demonstrating safety and efficacy, this treatise will not make the job effortless, but it will provide a framework and structure for safety evaluation to proceed in a rational way. For the regulatory scientist, the book provides the guidance necessary for a field of therapeutics that is ever changing. For scientists who are intimately involved with biopharmaceutical development, a copy of the book for their personal library is mandatory. Those who may not be intimately involved in biopharmaceutical development but may have an interest in the progress of a biotherapeutic agent will find the book a valuable resource and a reminder for the need of evaluating the safety of biotherapeutics by looking at each biopharmaceutical on a caseby-case approach.