Single dose acute toxicity studies

The requirement for conventional single dose acute toxicity testing prior to first-in-human studies was removed from the international pharmaceutical guidelines, ICH M3, in 2009. This was a landmark change as historically this was the only test in pharmaceutical development with death of the animals as an endpoint.

The regulatory change was in response to a data sharing initiative that we led with AstraZeneca and involving 17 other companies from across Europe. By sharing and analysing data from the companies on study designs we demonstrated that the single dose acute toxicity test had little scientific value in terms of identifying major organ toxicities and setting dose levels for subsequent studies, and that information could be provided from other studies already carried out as part of the drug development process, such as the maximum tolerated dose (MTD).

2007 2011 2012 2013
86%
(67/78)
58%
(76/132)
20%
(27/134)
16%
(15/93)

The impact of regulatory change: the proportion of clinical trial applications for drugs going into humans for the first time in the UK which contain the results from conventional single dose acute toxicity tests. The saving in animals is significant with up to 100 rodents used per drug for these tests. 

We were also able to challenge the use of single dose acute toxicity tests to support the management of overdose in Phase 3 trials and for registration following a survey of international poison centres and discussions with regulators which showed that the studies were not used by clinicians or regulators for the assessment of pharmaceutical overdose.

Chapman K and Robinson S. (2007). Challenging the Regulatory Requirement for Acute Toxicity Studies in the Development of New Medicines: Workshop Report. NC3Rs, London.

Robinson S, et al. (2008). A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development. Regulatory Toxicology and Pharmacology 50(3): 345-352. doi:10.1016/j.yrtph.2007.11.009

Robinson S and Chapman K. (2009). Are acute toxicity studies required to support overdose for new medicines? Regulatory Toxicology and Pharmacology 55(1): 110. doi:10.1016/j.yrtph.2009.06.012

Chapman K, Creton S et al. (2010). The value of acute toxicity studies to support the clinical management of overdose and poisoning: a cross-discipline consensus. Regulatory Toxicology and Pharmacology 58(3): 354-359. doi:10.1016/j.yrtph.2010.07.003

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