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Challenging the regulatory requirement for conventional acute toxicity studies in pharmaceutical drug development
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Abstracts / Toxicology 231 (2007) 91–99
Reference Cockshott, A., Evans, P., Ryan, C.A., Gerberick, G.F., Betts, C.J., Dearman, R.J., Kimber, I., Basketter, D.A., 2006. Hum. Exp. Toxicol. 25, 387–394.
doi:10.1016/j.tox.2006.11.017 Challenging the regulatory requirement for conventional acute toxicity studies in pharmaceutical drug development Sally Robinson 1 , Deborah Ockert 2 , Petet Stei 3 , David Dreher 4 , Kev Somers 5 , Elizabeth Donald 6 , Ann 7 8 Lampo , Sophie Kervyn , Nigel Pickersgill 9 , Vicente Nogues 10 , Kamil Nahas 11 , Mathias Festag 12 , Pascale Brunel 13 , Sally Old 14 , Claudia Stark 15 , Jean-Luc Delongeas 16 , Kathryn Chapman 17 E-mail address: [email protected] (S. Robinson). 1 Safety
Assessment, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK 2 AltanaPharma, Germany 3 Boehringer Ingelheim, Germany 4 Covance, UK 5 GSK, UK 6 Charles River PCS Edinburgh, UK 7 JandJ PRD Europe, Belgium 8 Lilly, Belgium 9 MDS Pharma Services, France 10 Novartis, Switzerland 11 Pfizer, France 12 Roche, Switzerland 13 Sanofi Aventis, France 14 Sanofi Aventis, UK 15 Schering, Germany 16 Servier, France 17 National Centre for the Replacement, Refinement and Reduction of Animals in Research, UK Acute toxicity studies in animals are usually performed to support the registration of any pharmaceutical intended for human use. The main objective of these studies is to identify a dose causing major adverse effects (often involving an estimation of the minimum dose causing lethality), usually in rodents, following a single dose up to a limit of 2000 mg/kg, or the maximum technically achievable. In pharmaceutical drug development, this is the only study type where lethality is a defined endpoint as documented in regulatory guidelines. The information obtained may be used to select the dose levels in the first studies in man and to give an indication of the likely effects of acute overdose in humans, but since it often does not include histopathological or toxicokinetic evaluation its clinical usefulness is questionable. A working party representing the pharmaceutical industry was formed in 2003 in order to assess the relevance of the data derived from conventional acute toxicity studies in rodents. The aim of the working group is to facilitate co-operation and data sharing on conventional acute toxicity studies, and to review how
acute toxicity data are gathered and used across the pharmaceutical industry. The objectives include agreeing a harmonised industry approach for the short term focussing on reduction and refinement of study design. An initial data sharing exercise on the approaches used within individual companies indicated significant scope for reduction through harmonisation (Robinson et al., 2005). A further objective is to develop a strategy for challenging the guidelines on the requirement for conventional acute toxicity where lethality is a defined endpoint, leading ultimately to replacement. The working party has undertaken a data sharing exercise to assess the value of conventional acute toxicity data in setting the dose levels in the first clinical trials in man. The results of this data sharing on over 40 compounds that entered clinical trails in man will be described along with the recommendation that these studies should not be a requirement at this stage of drug development. Such an approach would lead to a significant reduction in the numbers of studies performed and animals used due to compound attrition during the development process. Discussions are ongoing with regulatory authorities with the proposal that this topic may be addressed under ICH discussions. The ultimate goal of the working party is replacement and work is ongoing to address the value of acute toxicity data in animals in supporting overdose in man. The approach undertaken by the working party illustrates replacement may not necessarily require development of in vitro alternatives but may also be achieved by scientific evaluation of the reasons and value of the testing. Reference Robinson, S., Delongeas, D.-L., Donald, E., Dreher, D., Guittin, P., Kervyn, S., Lampo, A., Nogues, V., Ockert, D., Old, S., Pickersgill, N., Robinson, V., Somers, K., Stadler, J., Starkl, C., 2005. pp. 10–15 http://www.lal.org.uk/pdffiles/FELASA/Section1.pdf.
doi:10.1016/j.tox.2006.11.018 Approaches to minimise animal use in inhalation toxicity studies Simon Chivers E-mail address: [email protected]. Syngenta Central Toxicology Laboratory, Alderley park, Macclesfield, Cheshire SK10 4TJ, United Kingdom No validated in vitro alternatives for inhalation toxicity assessment are available. However, careful study design and consideration of the test guidelines and classification criteria, allow us to minimise the number of
Abstracts / Toxicology 231 (2007) 91–99
Reference Cockshott, A., Evans, P., Ryan, C.A., Gerberick, G.F., Betts, C.J., Dearman, R.J., Kimber, I., Basketter, D.A., 2006. Hum. Exp. Toxicol. 25, 387–394.
doi:10.1016/j.tox.2006.11.017 Challenging the regulatory requirement for conventional acute toxicity studies in pharmaceutical drug development Sally Robinson 1 , Deborah Ockert 2 , Petet Stei 3 , David Dreher 4 , Kev Somers 5 , Elizabeth Donald 6 , Ann 7 8 Lampo , Sophie Kervyn , Nigel Pickersgill 9 , Vicente Nogues 10 , Kamil Nahas 11 , Mathias Festag 12 , Pascale Brunel 13 , Sally Old 14 , Claudia Stark 15 , Jean-Luc Delongeas 16 , Kathryn Chapman 17 E-mail address: [email protected] (S. Robinson). 1 Safety
Assessment, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK 2 AltanaPharma, Germany 3 Boehringer Ingelheim, Germany 4 Covance, UK 5 GSK, UK 6 Charles River PCS Edinburgh, UK 7 JandJ PRD Europe, Belgium 8 Lilly, Belgium 9 MDS Pharma Services, France 10 Novartis, Switzerland 11 Pfizer, France 12 Roche, Switzerland 13 Sanofi Aventis, France 14 Sanofi Aventis, UK 15 Schering, Germany 16 Servier, France 17 National Centre for the Replacement, Refinement and Reduction of Animals in Research, UK Acute toxicity studies in animals are usually performed to support the registration of any pharmaceutical intended for human use. The main objective of these studies is to identify a dose causing major adverse effects (often involving an estimation of the minimum dose causing lethality), usually in rodents, following a single dose up to a limit of 2000 mg/kg, or the maximum technically achievable. In pharmaceutical drug development, this is the only study type where lethality is a defined endpoint as documented in regulatory guidelines. The information obtained may be used to select the dose levels in the first studies in man and to give an indication of the likely effects of acute overdose in humans, but since it often does not include histopathological or toxicokinetic evaluation its clinical usefulness is questionable. A working party representing the pharmaceutical industry was formed in 2003 in order to assess the relevance of the data derived from conventional acute toxicity studies in rodents. The aim of the working group is to facilitate co-operation and data sharing on conventional acute toxicity studies, and to review how
acute toxicity data are gathered and used across the pharmaceutical industry. The objectives include agreeing a harmonised industry approach for the short term focussing on reduction and refinement of study design. An initial data sharing exercise on the approaches used within individual companies indicated significant scope for reduction through harmonisation (Robinson et al., 2005). A further objective is to develop a strategy for challenging the guidelines on the requirement for conventional acute toxicity where lethality is a defined endpoint, leading ultimately to replacement. The working party has undertaken a data sharing exercise to assess the value of conventional acute toxicity data in setting the dose levels in the first clinical trials in man. The results of this data sharing on over 40 compounds that entered clinical trails in man will be described along with the recommendation that these studies should not be a requirement at this stage of drug development. Such an approach would lead to a significant reduction in the numbers of studies performed and animals used due to compound attrition during the development process. Discussions are ongoing with regulatory authorities with the proposal that this topic may be addressed under ICH discussions. The ultimate goal of the working party is replacement and work is ongoing to address the value of acute toxicity data in animals in supporting overdose in man. The approach undertaken by the working party illustrates replacement may not necessarily require development of in vitro alternatives but may also be achieved by scientific evaluation of the reasons and value of the testing. Reference Robinson, S., Delongeas, D.-L., Donald, E., Dreher, D., Guittin, P., Kervyn, S., Lampo, A., Nogues, V., Ockert, D., Old, S., Pickersgill, N., Robinson, V., Somers, K., Stadler, J., Starkl, C., 2005. pp. 10–15 http://www.lal.org.uk/pdffiles/FELASA/Section1.pdf.
doi:10.1016/j.tox.2006.11.018 Approaches to minimise animal use in inhalation toxicity studies Simon Chivers E-mail address: [email protected]. Syngenta Central Toxicology Laboratory, Alderley park, Macclesfield, Cheshire SK10 4TJ, United Kingdom No validated in vitro alternatives for inhalation toxicity assessment are available. However, careful study design and consideration of the test guidelines and classification criteria, allow us to minimise the number of