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Scientific Viewpoints in Ocular Toxicity Assessment: Depature from Conventional Practice.
Onodera, H.1), Sasaki, S.2), Otake, S.3), Tomohiro, M.4), Shibuya, K.5) and Nomura, M.6)
1) Pharmaceutical & Medical Devices Agency
2) Abbvie GK
3) Mitsubishi Chemical Medience Corporation
4) Alcon Japan Ltd.,
5) Nippon Institute for Biological Science
6) Ina Research Inc.
Animal Eye Research, 32: 3-13, 2013.
Abstract: Humans commonly obtain approximately 80% of external information from vision. Since quality of life markedly decreases with loss of vision, risk assessment for visual toxicity of new drugs is extremely important. However, the ICH S4 guideline for nonclinical toxicity study of new drugs only includes very limited description for ophthalmologic examinations, and data submission only according to this guideline is not always considered sufficient for risk assessment of ocular toxicity. The eye is an assembly of many specialized sub-organs which have specific function, and integral maintenance of homeostasis in the eye plays an important role of visual function. When only a part of integrity of function is lost, overall function of the eye might be commonly disturbed. Therefore, understanding of anatomy and physiology of these sub-organs may help to know mechanisms of observed ocular changes. In ophthalmologic examinations in nonclinical toxicity studies, it is vital to understand principles and features of each examination. Comparisons of findings between pre and post drug treatment as well as considerations of species differences, strain differences, age differences, and location of abnormalities should be essential. In addition, many kinds of spontaneous ocular findings are well known in experimental animals. To identify treatment-related changes from spontaneous findings, mastering basic skills for ophthalmologic examinations and taking advantage of collection of background data is necessary. To extrapolate to human, ocular findings obtained from animal should be evaluated based on their clinical significances. For preparation of histopathological samples, careful sampling of organs and appropriate selection of fixatives is important. To accurately orient ocular lesions in the specimen for histopathological examinations, discussions prior to necropsy among ophthalmologists, gross necropsy pathologists and histopathology technicians should be effective and helpful. Final diagnosis of ocular toxicity only based on histopathological findings does not always mean definitive, and comprehensive evaluation with information obtained from various examinations, mainly ophthalmologic examinations, should be made. In conclusion, for risk assessment of ocular toxicity, integrated judgments from all examination data in nonclinical toxicity studies are required, and therefore, ophthalmologists, as well as study director (toxicologists), clinical sign investigators, histopathology technicians and pathologists should share examination results, cooperate and act even more closely one another.
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