Abstract
Professor Gerhard Zbinden recognized in the 1970s that the standards of the day for testing new candidate drugs in preclinical toxicity studies failed to identify acute pharmacodynamic adverse events that had the potential to harm participants in clinical trials. From his vision emerged the field of safety pharmacology, formally defined in the International Conference on Harmonization (ICH) S7A guidelines as “those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above.” Initially, evaluations of small-molecule pharmacodynamic safety utilized efficacy models and were an ancillary responsibility of discovery scientists. However, over time, the relationship of these studies to overall safety was reflected by the regulatory agencies who, in directing the practice of safety pharmacology through guidance documents, prompted transition of responsibility to drug safety departments (e.g., toxicology). Events that have further shaped the field over the past 15 years include the ICH S7B guidance, evolution of molecular technologies leading to identification of new therapeutic targets with uncertain toxicities, introduction of data collection using more sophisticated and refined technologies, and utilization of transgenic animal models probing critical scientific questions regarding novel targets of toxicity. The collapse of the worldwide economy in the latter half of the first decade of the twenty-first century, continuing high rates of compound attrition during clinical development and post-approval and sharply increasing costs of drug development have led to significant strategy changes, contraction of the size of pharmaceutical organizations, and refocusing of therapeutic areas of investigation. With these changes has come movement away from dedicated internal safety pharmacology capability to utilization of capabilities within external contract research organizations. This movement has created the opportunity for the safety pharmacology discipline to come “full circle” and return to the drug discovery arena (target identification through clinical candidate selection) to contribute to the mitigation of the high rate of candidate drug failure through better compound selection decision making. Finally, the changing focus of science and losses in didactic training of scientists in whole animal physiology and pharmacology have revealed a serious gap in the future availability of qualified individuals to apply the principles of safety pharmacology in support of drug discovery and development. This is a significant deficiency that at present is only partially met with academic and professional society programs advancing a minimal level of training. In summary, with the exception that the future availability of suitably trained scientists is a critical need for the field that remains to be effectively addressed, the prospects for the future of safety pharmacology are hopeful and promising, and challenging for those individuals who want to assume this responsibility. What began in the early part of the new millennium as a relatively simple model of testing to assure the safety of Phase I clinical subjects and patients from acute deleterious effects on life-supporting organ systems has grown with experience and time to a science that mobilizes the principles of cellular and molecular biology and attempts to predict acute adverse events and those associated with long-term treatment. These challenges call for scientists with a broad range of in-depth scientific knowledge and an ability to adapt to a dynamic and forever changing industry. Identifying individuals who will serve today and training those who will serve in the future will fall to all of us who are committed to this important field of science.
“1. Don’t do something just because you can.
2. Don’t do something just because it has always been done.
3. Don’t do something just because others do it.”
“4. Don’t do something because (you believe) it is expected.
5. Don’t do something the results of which cannot be interpreted.
6. Do something because there is a reasonable expectation it will provide knowledge necessary for an accurate decision.”
Gerhard Zbinden and Robert Hamlin (Hamlin 2006)
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Abbreviations
- ABPI:
-
Association of the British Pharmaceutical Industry
- ADRs:
-
Adverse Drug Reactions
- AEs:
-
Adverse Events
- APD:
-
Action Potential Duration
- BfArM:
-
Bundesinstitut für Arzneimittel und Medizinprodukte which is the Federal Institute for Drugs and Medical Devices
- CFR:
-
Code of Federal Regulations
- CiPA:
-
Comprehensive In vitro Proarrhythmia Assay
- CNS:
-
Central Nervous System
- CPMP:
-
Committee for Proprietary Medicinal Products
- CROs:
-
Contract Research Organizations
- CSRC:
-
Cardiac Safety Research Consortium
- DSP:
-
Diplomate in Safety Pharmacology
- ECG:
-
Electrocardiogram
- ECVAM:
-
European Centre for the Validation of Alternative Methods
- EFPIA:
-
European Federation of the Pharmaceutical Industry Association
- eIND:
-
Exploratory Investigational New Drug Application
- EMEA:
-
European Medicines Agency
- EU:
-
European Union
- EWG:
-
Expert Working Group
- FDA:
-
United States Food and Drug Administration
- GLP:
-
Good Laboratory Practice
- hERG:
-
human Ether-a-go-go-Related Gene
- ICH:
-
International Conference on Harmonization
- ILSI:
-
International Life Sciences Institute
- IWG:
-
Implementation Working Group
- HESI:
-
Health and Environmental Sciences Institute
- IND:
-
Investigational New Drug Application
- iPSCs:
-
Induced pluripotent stem cells
- JACL:
-
Japan Association of Contract Laboratories for Safety Evaluation
- JNDA:
-
Japanese New Drug Applications
- JPMA:
-
Japanese Pharmaceutical Manufacturers Association
- MHLW:
-
Ministry of Health, Labour and Welfare
- MHW:
-
Ministry of Health and Welfare
- NCEs:
-
New Chemical Entities
- NDAs:
-
New Drug Applications
- PhRMA:
-
Pharmaceutical Research and Manufacturers of America
- Q&As:
-
Questions and Answers
- QT:
-
Duration of the QT interval of the cardiac electrocardiogram
- QT PRODACT:
-
QT Interval Prolongation: Project for Database Construction
- R&D:
-
Research and Development
- SEND:
-
Standard for Exchange of Nonclinical Data
- SP:
-
Safety pharmacology
- SPS:
-
Safety Pharmacology Society
- JSPS:
-
Japanese Safety Pharmacology Society
- TDP:
-
Therapeutic Products Directorate
- TQT:
-
Clinical Thorough QT study
- USA:
-
United States of America
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The authors are grateful to Drs. Gerd Bode and Joseph J. DeGeorge for their review of the manuscript and helpful comments.
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Bass, A.S., Hombo, T., Kasai, C., Kinter, L.B., Valentin, JP. (2015). A Historical View and Vision into the Future of the Field of Safety Pharmacology. In: Pugsley, M., Curtis, M. (eds) Principles of Safety Pharmacology. Handbook of Experimental Pharmacology, vol 229. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-46943-9_1
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Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-46942-2
Online ISBN: 978-3-662-46943-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)