Advanced Issue Resolution in Safety Pharmacology

Mary Jeanne Kallman & Michael K. Pugsley
Published in: Academic Press
Release Year: 2019
ISBN: 978-0128-1-2206-8
Pages: 360
Edition: 1st
File Size: 11 MB
File Type: pdf
Language: English

Description of Advanced Issue Resolution in Safety Pharmacology

The inception of this book was fostered by a need for discussion of more advanced topics in safety pharmacology data collection and the application of those data for clinical translation. Several texts have been published to address the regulatory drivers from the ICH S7A and S7B guidelines that were approved in 2000 and 2005, respectively. The ICH guidelines require cardiovascular, central nervous system (CNS), and respiratory evaluation, as severe alterations in these biological systems could lead to severe safety consequences or death. Earlier safety pharmacology texts focused primarily on the three required components of a safety pharmacology submission necessary to start the clinical testing of potential new compounds.
These texts, however, are without emphasis on secondary systems, such as renal, gastrointestinal, and immune function, which were conducted more frequently prior to the publication of the ICH S7A guidance. More recently, in an effort to better understand the sufficiency of standard required safety pharmacology assessments, investigators have examined the predictability of preclinical data to clinical issues. Toxicity issues that arise in drug development are scrutinized by additional testing as a component of a pathway forward for predicted issues. The main focus of this book is to identify the more advanced laboratory alternatives for understanding preclinical effects and how additional investigative and mechanistic data can be used to understand the clinical significance of preclinical findings. Although the three primary areas for evaluation in the required safety pharmacology package are important, many other functions can also be important for guiding compound development.
Methods for conducting assessments of preclinical functioning and how to apply those data to better understand issues are the primary topic of Advanced Issue Resolution in Safety Pharmacology book. A review of the history of early regulation of approval and registration of new drugs in the United States (Chhabra et al., 2005) is a reminder that the failures of safety predictions for the development of new compounds were the drivers for regulations and registration requirements. Much of early regulation such as the Kefauver Harris Amendment (Drug Efficacy Amendment) in 1962 to the Federal Food, Drug, and Cosmetic Act was a result of the incidence of congenital abnormalities associated with thalidomide use in pregnant women for morning sickness (Peltzman, 1973). The scientific resolution of issues that arise during compound development is challenging and requires stellar scientific logic. Successful, cost-effective, and focused issue resolution is the  hallmark of outstanding pharmaceutical scientists who conceptualize a clear path to understanding the critical data and the relevance of those data to translation in the clinic.
These pharmaceutical scientists will be prized by their drug companies and equipped with knowledge of what the scientist can achieve. The vision for resolution strategies (Valentin et al., 2009) is not taught in graduate school but rather develops from the evolution of basic science knowledge with industry experience. It might also be argued that clinical knowledge is a critical tool that many basic science students are not always exposed to in didactic courses but must learn from interacting with clinical experts. The translation of preclinical science to the clinical environment is under constant discussion, and the current laboratory tools and methodologies to resolve scientific issues change continually. Advanced Issue Resolution in Safety Pharmacology book will address some of the content areas that have not been thoroughly discussed previously, i.e., stereotypic behavior and progressive ratio testing.
All of the chapters will discuss steps toward issue resolution and provide clear examples of how the specific techniques have been successfully used in issue resolution. Readers should find some chapters that discuss areas with which they are not familiar discussed in detail in the past or thought about recently but areas that could impact specific issues in drug development. Knowing when an issue is unimportant or worthy of further exploration is not always clear from the past. One approach for understanding current drug development is to summarize how the demo-graphics for regulatory approval are changing.
Recent data posted by the FDA on their government website provide characterization of activity for new drug application (NDA) approvals in 2017. Although these data do not necessarily dictate the future shape of drug development in 2018, they do reflect a potential trend within the pharmaceutical industry. Forty-six NDAs were reviewed in 2017 and 85% of those reviews led to drug approval. A success rate of 85% should be encouraging to those seeking approval of an NDA. Between 2008 and 2017, FDA reviewed on average of 31 novel drugs per year. In 2016 considerably fewer drugs were reviewed, only 23. Some have even suggested that new drugs and novel treatments may be waning. The lower volume in 2016 appears to not represent a new trend but possibly indicates an effort to readjust pharmaceutical industry submission approaches and internal industry strategies.
The types of drugs approved may also suggest a transition in the drugs in development. Of the 46 drugs approved in 2017, 37% were breakthrough therapies and roughly one-third were first in class. None of the drugs in development moved through the pre–Investigational New Drug (IND) and the three phases of clinical development without issue resolution for continued compound progression to final approval. As the industry continues to pursue the registration of novel drugs and novel mechanisms of action, the emphasis on issue resolution seems imperative. In the situation where a novel mechanism is the focus, the literature or previous wisdom may not predict issues in advance of pre-clinical testing and earlier clinical findings; therefore, teams will have to identify new techniques and approaches for issue resolution.
All drugs in the approved marketplace likely have had issues that have occurred during development. It could be concluded that novel approaches may be the most challenging for issue resolution but offer the highest potential for marketplace success when a drug is approved.
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