Abstract
Drug development over the years has become a much more difficult and challenging process, as both scientific and regulatory issues have led this process to become more defined, more expensive, and more risky, and this is certainly true of the drug safety aspects of drug development. This, however, is as it should be because society expects new drugs with a higher degree of efficacy but with a lower degree of risk. Up into the 1980s, drug development researchers were primarily investigating and testing only small chemical molecules. However, as we entered into the era of the ‘omics’, targeted drug development and targeted drug delivery at the molecular became available, as did a better understanding of the disease process at the molecular level. Scientifically, a wide range of large molecules, including proteins, peptides, and monoclonal antibodies, began to be investigated, leading to treatment modalities that were both new and novel, and which were much more effective. In today’s world, the reward for bringing a new drug successfully to market can be billions of dollars a year in revenue for the company. However, the overall success rate from drug conception to drug approval remains exceptionally low. The cost and time for getting a new drug to market means that the decision makers in those companies focusing on this activity must be fully committed and aware of the testing components that make up the drug developmental process, including drug safety evaluation. They should exhibit intelligence (both practical and scientific), nimbleness, and creativity to ensure that an effective and streamlined approach is undertaken to minimize cost and time while maximizing the opportunity for success.
This new text, Drug Safety Evaluation, 4th Edition, continues the tradition of excellence of the previous three editions but its content has been expanded over that of the third edition (published in 2017). At 960 pages and 36 chapters, it is about 40 pages larger than the third edition and includes three new chapters and several chapters with expanded content. The three new chapters, Electronic Records, Reporting, and Submission: eCTD and SEND, Toxicogenomics, and Adverse Outcome Pathway in Drug Safety Assessment provide important guidance and information that were missing in the earlier editions. Chapters 2 (Regulation of Human Pharmaceutical Safety: Routes to Human Use and Market), 17 (Histopathology and Clinical Pathology in Nonclinical Pharmaceutical Safety Assessment), and 24 (Special Case Products: Drugs for Treatment of Cancer) have been greatly expanded to add value and clarity to the reader. All other chapters appear to have been updated to some degree along with a number of new citations throughout the text.
While a number of fine texts discussing aspects of drug development and drug safety evaluation have been published over the years, none have covered such a wide range of areas quite like this text. Indeed, this may be the most inclusive text of its type to be published in drug safety testing. The authors have cast a wide net to select topics that can be critical to the drug development process but which are not always included in similar texts. The chapters are presented in a logical pattern, beginning with discussions on the drug development process, the history of the regulations involved with human safety testing, and submission of eCTD and SEND documents, followed by specific discussions on the various types of required drug safety testing (pilot testing. repeat dose studies. genotoxic studies, development and reproductive studies, carcinogenicity studies, irritation and local tissue tolerance studies, safety pharmacology studies, inhalation and dermal studies, juvenile and pediatric studies, and the use of imaging agents and radiopharmaceuticals). The final chapters provide in-depth discussions relating to areas such as occupational toxicology, human tolerance and safety in clinical trials, post-marketing safety evaluation, and statistics. The five appendices presented provide a plethora of very useful and generally hard to find information regarding regulatory and toxicological acronyms, a lexicon of clinical observations observed in preclinical animal studies, regulatory internet addresses, a glossary of terms used in the clinical evaluation of therapeutic agents, common vehicles used in preclinical testing of therapeutic agents, and a global directory of worldwide contract toxicology laboratories.
This text should almost be required reading for the experienced professional involved with any of the aspects associated with drug development and drug safety as it relates to both the theory and practicality of these processes. It would also clearly be beneficial reading to the graduate students and younger professionals in those areas as it provides a basic clarity for understanding and applying these concepts in their future professional development.
However, this reviewer noted some defects within the text. Although every table and appendix was not thoroughly reviewed, a spot check determined that the quality review of several tables and appendices missed some errors which I could identify. Some examples include: Table 1.2 for AstraZeneca lists 4 best selling drugs rather than the 3 that the table mentions and with no sales value for Nexium; Table 1.2 also shows two footnotes but only one is identified in the table; Table 1.9 presents an * for CNS safety pharmacology testing but with no explanation of what the * is referring to; Section 17.2.4 is entitled Oy Examination of Brain for CNS Active Drugs but is Oy the correct terminology (referring to Olney lesions)? In addition, Appendix F (Global Directory of Contract Toxicology Labs) has a number of errors including misspelling MPI Research (MSI) under the Charles River heading and listing it twice and not including the Inotiv Gaithersburg, MD site. Also, many of the pages in the appendices are not numbered. Finally, while Section 2.2.2 presents a useful discussion of the events that led up to the passing of the 1938 Food, Drug, and Cosmetic Act, I would have liked to have seen more historical examples of ‘bad actors’ that showed that the 1906 Pure Food and Drug Act was insufficient in protecting the patient population. This could have included the deaths of the ‘radium girls of the 1920s (they painted radium on watch dials with self-luminous paint), Koremlu depilatory (containing thallium acetate), Lash Lure eyebrow and lash dye (containing para-phenylenediamine), and Gouraud’s Oriental Skin Cream (mercury chloride).
As a final note, in the field of toxicology, Dr. Shayne Gad has been one of the most prolific writers of our generation, encompassing a wide range of important topics in toxicology and drug safety and the current text will be his 53rd. Through private conversations, he has informed me that that will be his last text. If this is true (and I am not convinced that it is), then those of us in this industry should extend our deep thanks and appreciation to him for his tremendous publication accomplishments over the past 40 years. And his forethought for enlisting Dexter Sullivan as the co-author for the current edition suggests that a continuity of authorship has been established to ensure that future editions of this important publication will continue in the future.