Potentials and limitations of nonclinical safety assessment for predicting clinical adverse drug reactions: correlation analysis of 142 approved drugs in Japan

Chihiro Tamaki; Takashi Nagayama; Masamichi Hashiba; Masato Fujiyoshi; Masanori Hizue; Hiroshi Kodaira; Minoru Nishida; Kazuhiko Suzuki; Yoshiharu Takashima; Yamato Ogino; Daisaku Yasugi; Yasuo Yoneta; Shigeru Hisada; Takako Ohkura; Kazuichi Nakamura

doi:10.2131/jts.38.581

Original Article

Potentials and limitations of nonclinical safety assessment for predicting clinical adverse drug reactions: correlation analysis of 142 approved drugs in Japan

Chihiro Tamaki, Takashi Nagayama, Masamichi Hashiba, Masato Fujiyoshi, Masanori Hizue, Hiroshi Kodaira, Minoru Nishida, Kazuhiko Suzuki, Yoshiharu Takashima, Yamato Ogino, Daisaku Yasugi, Yasuo Yoneta, Shigeru Hisada, Takako Ohkura, Kazuichi Nakamura

Author information

Chihiro Tamaki
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Preclinical, Japan Regulatory Affairs, Drug Development, Eli Lilly Japan K.K.
Takashi Nagayama
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Non-Clinical Development, UCB Japan Co., Ltd.
Masamichi Hashiba
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Development Research, Mochida Pharmaceutical Co., Ltd.
Masato Fujiyoshi
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Masanori Hizue
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
DSRD-Tokyo, Pfizer Japan Inc.
Hiroshi Kodaira
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Development Planning and Coordination, Pharmaceutical Research & Development, Yakult Honsha Co., Ltd.
Minoru Nishida
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Research & Development Center, Fuso Pharmaceutical Industries, Ltd.
Kazuhiko Suzuki
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Translational Sciences, Novartis Pharma K.K.
Yoshiharu Takashima
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Preclinical Experts, Regulatory Affairs, Product Development Department, Bayer Yakuhin, Ltd.
Yamato Ogino
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Drug Research Department, Toa Eiyo Ltd.
Daisaku Yasugi
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Research & Development Center, Fuso Pharmaceutical Industries, Ltd.
Yasuo Yoneta
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Pharmacokinetics and Safety Research Department, Kaken Pharmaceutical Co., Ltd.
Shigeru Hisada
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Developmental Research Center, ASKA Pharmaceutical Co., Ltd.
Takako Ohkura
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Department of Clinical Development, Maruishi Pharmaceutical Co., Ltd.
Kazuichi Nakamura
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association
Global Regulatory Affairs Department, Shionogi & Co., Ltd.

Keywords: Adverse drug reactions, Toxicity, Nonclinical testing, Correlation, Approved drugs

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Supplementary material

2013 Volume 38 Issue 4 Pages 581-598

DOI https://doi.org/10.2131/jts.38.581

Details

Abstract

The objective of this study was to elucidate the range of abilities of nonclinical safety assessment for predicting adverse drug reactions (ADRs) in humans. The dataset included 1256 ADRs with an incidence rate of 5% or more collected from 142 drugs approved in Japan from 2001 to 2010 (excluding anticancer agents and vaccines). Gastrointestinal, neurological and hepatobiliary ADRs were relatively common, followed by hematological, cutaneous, systemic and cardiovascular ADRs in the dataset. The analysis revealed that 48% of ADRs were predictable based on a comprehensive nonclinical safety assessment considering animal toxicity. Hematological and ocular ADRs, infection, and application site reactions showed a correlation of more than 70%, while musculoskeletal, respiratory and neurological ADRs showed a correlation of less than 30%. In addition to subjective patient perceptions, several laboratory parameters routinely monitored both in animals and humans showed a lower correlation, e.g., abnormalities in hepatobiliary and metabolic parameters, and blood pressure increase. Large molecule drugs showed lower correlation than small molecule drugs; ADRs were observed in various organs and consideration of pharmacological action did not significantly contribute to the prediction. It was also confirmed that the current standard of toxicology testing regarding dosing duration and dose level is adequate to detect concordant animal toxicity. This study collectively demonstrated a significant value of nonclinical safety assessment in predicting ADRs in humans. It also identified the subset of ADRs with poor predictability, highlighting the need for advanced testing that enables successful translation of animal toxicity to clinical settings with better accuracy and sensitivity.

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