This week we are pleased to welcome Dr. Arianna Bassan as a guest contributor to the blog.
The recently published draft addendum of the ICH S1B guideline1 introduces a weight-of-evidence (WoE) approach to assess human carcinogenic potential of small molecule pharmaceuticals and determine whether a 2-year rat carcinogenicity study would add value. Application of this integrated analysis “would reduce the use of animals in accordance with the 3Rs (reduce/refine/replace) principles, and shift resources to focus onto generating more scientific mechanism-based carcinogenicity assessments, while promoting safe and ethical development of new small molecule pharmaceuticals”1. The WoE approach described in the S1B addendum is based on a comprehensive assessment of relevant factors including:
- Data that inform carcinogenic potential based on drug target biology and the primary pharmacologic mechanism of the compound including carcinogenicity information available on the drug class
- Results from secondary pharmacology screens, especially those that inform carcinogenic risk
- Histopathology data from repeated dose toxicity studies completed with the test agent, with particular emphasis on the long-term rat study including exposure margin assessments
- Evidence for hormonal perturbation
- Genetic toxicology study data
- Evidence of immune modulation
Instem has recently initiated a new collaborative working group (WG) to develop a protocol (i.e., standardized approach) that can support the carcinogenicity WoE integrated assessment in a transparent, consistent, and defendable manner. The group aims at developing a high-level protocol that integrates in silico methods while assembling information from the different WoE factors described in the S1B draft addendum. The WG activities are building upon the extensive work already completed as part of the in silico toxicology protocol project2 that may feed the S1B higher-level, fit-for-purpose protocol with previous outcome such as:
- the genetic toxicology in silico protocol3 that may support the corresponding S1B WoE factor;
- the principles to evaluate reliability and confidence of a toxicity assessment4 as the integration of data should be complemented by evaluation of reliability and confidence scores based on the quality of the information used to derive the assessment and the overall uncertainty of such an assessment;
- the framework based on the 10 key characteristics (KCs) of carcinogens5 that can sustain the organization of granular information to support each of the WoE areas and help provide a comprehensive assessment based upon what we currently know about tumorigenesis.
The very first objective of the S1B consortium WG is a high-level conceptual paper that describes how the S1B WoE assessment may take advantage of a decision support system making use of in silico toxicology protocols. This work will also include mapping the KCs onto the S1B WoE factors and describing each WoE factor in terms of the pieces and elements that would define the assessment protocol.
For more information on this collaboration or related projects, please contact Glenn Myatt (firstname.lastname@example.org).
1 Addendum to the ICH guideline S1B on testing for carcinogenicity of pharmaceuticals Draft version Endorsed on 10 May 2021, Currently under public consultation, https://www.ich.org/page/safety-guidelines
2 Myatt, G.J., Ahlberg, E., Akahori, Y., Allen, D., Amberg, A., Anger, L.T., Aptula, A., Auerbach, S., Beilke, L., Bellion, P., Benigni, R., Bercu, J., Booth, E.D., Bower, D., Brigo, A., Burden, N., Cammerer, Z., Cronin, M.T.D., Cross, K.P., Custer, L., Dettwiler, M., Dobo, K., Ford, K.A., Fortin, M.C., Gad-McDonald, S.E., Gellatly, N., Gervais, V., Glover, K.P., Glowienke, S., Van Gompel, J., Gutsell, S., Hardy, B., Harvey, J.S., Hillegass, J., Honma, M., Hsieh, J.-H., Hsu, C.-W., Hughes, K., Johnson, C., Jolly, R., Jones, D., Kemper, R., Kenyon, M.O., Kim, M.T., Kruhlak, N.L., Kulkarni, S.A., Kümmerer, K., Leavitt, P., Majer, B., Masten, S., Miller, S., Moser, J., Mumtaz, M., Muster, W., Neilson, L., Oprea, T.I., Patlewicz, G., Paulino, A., Lo Piparo, E., Powley, M., Quigley, D.P., Reddy, M.V., Richarz, A.-N., Ruiz, P., Schilter, B., Serafimova, R., Simpson, W., Stavitskaya, L., Stidl, R., Suarez-Rodriguez, D., Szabo, D.T., Teasdale, A., Trejo-Martin, A., Valentin, J.-P., Vuorinen, A., Wall, B.A., Watts, P., White, A.T., Wichard, J., Witt, K.L., Woolley, A., Woolley, D., Zwickl, C., Hasselgren, C., 2018. In silico toxicology protocols. Regul. Toxicol. Pharmacol. 96, 1–17. https://doi.org/10.1016/j.yrtph.2018.04.014
3 Hasselgren, C., Ahlberg, E., Akahori, Y., Amberg, A., Anger, L.T., Atienzar, F., Auerbach, S., Beilke, L., Bellion, P., Benigni, R., Bercu, J., Booth, E.D., Bower, D., Brigo, A., Cammerer, Z., Cronin, M.T.D., Crooks, I., Cross, K.P., Custer, L., Dobo, K., Doktorova, T., Faulkner, D., Ford, K.A., Fortin, M.C., Frericks, M., Gad-McDonald, S.E., Gellatly, N., Gerets, H., Gervais, V., Glowienke, S., Van Gompel, J., Harvey, J.S., Hillegass, J., Honma, M., Hsieh, J.-H., Hsu, C.-W., Barton-Maclaren, T.S., Johnson, C., Jolly, R., Jones, D., Kemper, R., Kenyon, M.O., Kruhlak, N.L., Kulkarni, S.A., Kümmerer, K., Leavitt, P., Masten, S., Miller, S., Moudgal, C., Muster, W., Paulino, A., Lo Piparo, E., Powley, M., Quigley, D.P., Reddy, M.V., Richarz, A.-N., Schilter, B., Snyder, R.D., Stavitskaya, L., Stidl, R., Szabo, D.T., Teasdale, A., Tice, R.R., Trejo-Martin, A., Vuorinen, A., Wall, B.A., Watts, P., White, A.T., Wichard, J., Witt, K.L., Woolley, A., Woolley, D., Zwickl, C., Myatt, G.J., 2019. Genetic toxicology in silico protocol. Regul. Toxicol. Pharmacol. 107, 104403. https://doi.org/10.1016/j.yrtph.2019.104403
4 Johnson, C., Anger, L.T., Benigni, R., Bower, D., Bringezu, F., Crofton, K.M., Cronin, M.T.D., Cross, K.P., Dettwiler, M., Frericks, M., Melnikov, F., Miller, S., Roberts, D.W., Suarez-Rodrigez, D., Roncaglioni, A., Lo Piparo, E., Tice, R.R., Zwickl, C., Myatt, G.J., 2022. Evaluating confidence in toxicity assessments based on experimental data and in silico predictions. Computational Toxicology 21, 100204. https://doi.org/10.1016/j.comtox.2021.100204 5 Tice, R.R., Bassan, A., Amberg, A., Anger, L.T., Beal, M.A., Bellion, P., Benigni, R., Birmingham, J., Brigo, A., Bringezu, F., Ceriani, L., Crooks, I., Cross, K., Elespuru, R., Faulkner, D., Fortin, M.C., Fowler, P., Frericks, M., Gerets, H.H.J., Jahnke, G.D., Jones, D.R., Kruhlak, N.L., Lo Piparo, E., Lopez-Belmonte, J., Luniwal, A., Luu, A., Madia, F., Manganelli, S., Manickam, B., Mestres, J., Mihalchik-Burhans, A.L., Neilson, L., Pandiri, A., Pavan, M., Rider, C.V., Rooney, J.P., Trejo-Martin, A., Watanabe-Sailor, K.H., White, A.T., Woolley, D., Myatt, G.J., 2021. In silico approaches in carcinogenicity hazard assessment: current status and future needs. Comput. Toxicol. 20, 100191. https://doi.org/10.1016/j.comtox.2021.100191