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Duration of Acute and Chronic Toxicity Testing in Animals (ICH S4A and S4B)

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Global Approach in Safety Testing

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 5))

Abstract

To support approval of pharmaceuticals for long-term use in humans, it is required that product safety is supported by acute and chronic toxicity studies in rodents and non-rodents. The duration of acute toxicity studies (S4A) and chronic rodent studies (S4B) was harmonised between the three ICH regions in 1991, whereas the process of harmonising the duration of non-rodent studies was initiated. The US FDA originally required studies of at least 12-month duration, whereas in Japan and EU studies of 6-month duration were considered acceptable as an ICH objective. In this chapter, the background for the ICH S4B guideline regarding the duration of non-rodent repeated-dose toxicity studies is explained and lessons learned are discussed. Since the guideline was issued in 1997, changes occurred in, e.g. the language of the European legislation, and the requirements for non-clinical studies to support clinical development have progressed within the ICH (M3): we therefore consider options such as prospective evaluation, biomarker-based mechanistic understanding, toxicokinetics and the use of evidence-based medicine to support further joint activities to harmonise the duration of non-rodent toxicity studies at the global level.

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Abbreviations

CMR:

Centre for Medicines Research (now Centre for Innovation in Regulatory Science CIRS)

CRO:

Contract Research Organisation

ECVAM:

European Centre for the Evaluation of Alternative Methods

EFPIA:

European Federation of Pharmaceutical Industries and Associations

EMEA:

European Agency for the Evaluation of Medicinal Products (now European Medicines Agency EMA)

EU:

European Union

EWG:

Expert Working Group

FDA:

United States Food and Drug Administration

ICH:

International Conference of Harmonization of Pharmaceutical for Human Use

JPMA:

Japanese Pharmaceutical Manufacturers Association

MHW:

Japanese Ministry of Health and Welfare (now Ministry of Health Labour and Welfare, MHLW)

NIH:

National Institutes of Health

PhRMA:

Pharmaceutical Research and Manufacturers of America

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Acknowledgement

We wish to acknowledge our colleagues Prof. Emeritus Jens S. Schou, Dr. Steven Spanhaak and Dr. Per Sjöberg for review and valuable discussion of this chapter.

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Authors and Affiliations

  1. Biopeople, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Per Spindler

  2. Pharmaparacelsus LLC, Gierle, Belgium

    Herman Van Cauteren

Authors
  1. Per Spindler
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  2. Herman Van Cauteren
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Corresponding author

Correspondence to Per Spindler .

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Editors and Affiliations

  1. , Section on Pharmacology, Toxicology, and, Medicines Evaluation Board, Graadt van Roggenweg 500, Utrecht, 3531 AH, Netherlands

    Jan Willem van der Laan

  2. , Drug Safety Testing, Merck Research Laboratories, Sumneytown Pike 770, West Point, 19486, Pennsylvania, USA

    Joseph J. DeGeorge

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© 2013 American Association of Pharmaceutical Scientists

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Spindler, P., Van Cauteren, H. (2013). Duration of Acute and Chronic Toxicity Testing in Animals (ICH S4A and S4B). In: van der Laan, J., DeGeorge, J. (eds) Global Approach in Safety Testing. AAPS Advances in the Pharmaceutical Sciences Series, vol 5. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5950-7_8

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