CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector J Infect Chemother (2011) 17:139–147 DOI 10.1007/s10156-010-0183-0 COMMITTEE REPORT Criteria for safety evaluation of antimicrobial agents Japanese Society of Chemotherapy • Antimicrobial Agents Safety Evaluation Standards Committee • Akira Watanabe • Yutaka Tokue • Nobuki Aoki • Tetsuro Matsumoto • Katsunori Yanagihara • Futoshi Higa • Hiroyuki Tsuge • Masahito Nagashima • Hiromi Matsuoka • Yuji Sasagawa • Masato Matsumoto • Kazuo Fujimaki • Kenji Taguchi • Mari Ariyasu • Norifumi Yamamoto • Otohiko Kunii • Kohya Shiba Received: 3 September 2010 / Accepted: 18 October 2010 / Published online: 6 January 2011 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2011. Open access under the Elsevier OA license. Keywords Safety evaluation criteria Á have been adopted in many clinical studies from immedi- Antimicrobial agent Á Clinical trial ately after their publication and are also cited in areas other than antimicrobial agents. Accumulated safety data based on the criteria have been submitted to the regulatory authorities in Japan for marketing approval applications. Principles and basic concepts on the safety evaluation No inquiries such as uncertainty about the safety evalua- of antimicrobial agents tions in clinical studies of antimicrobial agents have been made so far; therefore, the criteria seem to be recognized The Japanese Society of Chemotherapy criteria for widely, including by the regulatory authorities. assessment of adverse reactions and abnormal laboratory However, there is a concern that the JSC’s current cri- values associated with antibacterial agents in study subjects teria do not fit the present situation, because in recent new [1, 2] (hereinafter referred to as ‘‘JSC’s current criteria’’), drug development the results of overseas clinical studies A. Watanabe M. Nagashima Research Division for Development of Anti-Infective Agents, Pfizer Japan Inc, Tokyo, Japan Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan Y. Sasagawa Á M. Matsumoto Meiji Seika Kaisha Ltd, Tokyo, Japan Y. Tokue Infection Control and Prevention Center, K. Fujimaki Á K. Taguchi Gunma University Hospital, Maebashi, Japan Toyama Chemical Co., Ltd, Tokyo, Japan N. Aoki M. Ariyasu Shinrakuen Hospital, Niigata, Japan Shionogi & Co., Ltd, Osaka, Japan T. Matsumoto N. Yamamoto Department of Urology, School of Medicine, University of Sanofi-Aventis K.K., Tokyo, Japan Occupational and Environmental Health, Kitakyushu, Japan O. Kunii K. Yanagihara Teikyo University, Tokyo, Japan Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan K. Shiba The Jikei University School of Medicine, Tokyo, Japan F. Higa Department of Infectious, Respiratory, and Digestive Medicine, A. Watanabe (&) Faculty of Medicine, University of the Ryukyus, Okinawa, Japan Japanese Society of Chemotherapy, Nichinai Kaikan B1, 3-28-8 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan H. Tsuge Á H. Matsuoka e-mail: [email protected] Daiichi-Sankyo Co., Ltd, Tokyo, Japan 123 140 J Infect Chemother (2011) 17:139–147 have been used aggressively or global studies have been agents, followed by ‘‘respiratory, thoracic and mediastinal conducted. disorders,’’ ‘‘skin and subcutaneous tissue disorders,’’ The Antimicrobial Agents Safety Evaluation Standards ‘‘general disorders and administration site conditions,’’ Committee of the JSC (hereinafter, the ‘‘Committee’’) has ‘‘infections and infestations,’’ ‘‘musculoskeletal and con- developed a concept of ‘‘abnormal changes in laboratory nective tissue disorders,’’ and ‘‘nervous system disorders’’ values’’ while taking into account management of the (see Table 6). In order to individually define the severity of results of studies by overseas pharmaceutical companies. each adverse event, as is done with the CTCAE, the This concept was developed for the purpose of maintaining Committee assumed that a comprehensive analysis based consistency with Western safety evaluation from a global on clinical findings and epidemiological data for each viewpoint. With regard to adverse events in terms of specialized field would be necessary and that ensuring symptoms and findings, we have summarized the infor- universality would be difficult. Therefore, in our report we mation on adverse events in clinical studies of antimicro- decided to show comprehensive criteria for the assessment bial agents approved for marketing after 2005 (see of severity, regardless of the individual symptoms and find- Tables 6, 7) and discussed evaluation points for adverse ings. This concept was also based on the idea that the opinions events that occurred frequently in clinical studies of anti- of the physicians who actually take charge of clinical studies microbial agents. would be appropriate for the assessment of the severity of adverse events and their causal relationships. Abnormal changes in laboratory values Previously, when assessing whether or not changes in Criteria for safety evaluation of laboratory values laboratory values were adverse events, we classified them into two groups: a shift from a normal to an abnormal value Method for evaluation of abnormal changes or an aggravation from the abnormal value before admin- and adverse events istration. From the perspective of maintaining consistency with the evaluation of overseas clinical study data and in Criteria for abnormal changes in laboratory values are order to be concise, however, we have established an shown in Table 1. Based on these criteria, when laboratory assessment procedure that enables each laboratory test item values are within the range of abnormal changes, accom- to be evaluated by a Grade based on standard values for panying any adverse symptoms or findings, or possibly these items. Furthermore, in consideration that the JSC’s resulting in them, or requiring additional tests or treatment, current criteria have been adopted in many clinical studies they should be handled as adverse events, and the causal and results have accumulated, we fully analyzed the relationship with the investigational drug should be assessed. available data from clinical studies and avoided causing a Laboratory values are known to fluctuate in relation to large discrepancy from current evaluation results. In par- interindividual factors such as sex, age, and lifestyle, and ticular, the assessment results when defining abnormal intraindividual factors such as diurnal variation, type and changes as Grade 2 or higher according to the ‘‘Common timing of meals, physical exercise, body posture, and the Terminology Criteria for Adverse Events v 3.0 JCOG/ sexual cycle. Therefore, whether or not changes in labo- JSCO version’’ [3] (hereinafter referred to as the ratory values are assessed as adverse events should be ‘‘CTCAE’’), which are generally found to be similar to the determined by distinguishing them as physiological chan- JSC’s current criteria, the abnormal changes tended to be ges or pathological (adverse) changes, while taking com- consistent with the assessment results based on the JSC’s plete account of the background characteristics of the current criteria. We decided that the classification specified subject concerned, such as underlying disease and com- in the CTCAE could be used to promote the optimum plications, and baseline values of the tests and/or changes safety evaluation of antimicrobial agents. unique to the subject if he/she underwent periodic labora- Details of the establishment of criteria for abnormal tory tests before study participation. changes in laboratory values have been published in the Nonetheless, there may be cases where it is not appro- interim report of the Japanese Society of Chemotherapy, priate to simply identify individual abnormal changes in Antimicrobial Agents Safety Evaluation Standards Com- laboratory values and determine them to be adverse events. mittee [4]. Considering that abnormal changes in laboratory values involve the clinical background and adverse symptoms/ Symptoms/findings findings in the subject concerned, it is more important to comprehensively evaluate adverse events occurring in the Events related to ‘‘gastrointestinal disorders’’ are the most subject. In other words, when no diagnostic term can be frequent adverse events in clinical studies of antimicrobial defined for an adverse event, individual abnormal changes 123 J Infect Chemother (2011) 17:139–147 141 Table 1 Criteria for assessing abnormal changes in laboratory values as adverse events Laboratory tests Laboratory values to be reviewed for adopting as adverse events Red blood cell count (RBC) Male \3,500,000/mm3, female \3,200,000/mm3 Hemoglobin \10 g/dL Hematocrit Male \35%, female \30% White blood cell count (WBC) \3000/mm3. Increased values are not determined to be adverse events unless there is some special reason. It may be handled as neutrophil count decreased (\1,500/mm3) or lymphocytes decreased (\800/mm3) Eosinophil count C500/mm3,orC10% as % of eosinophil in WBC Allergic disease should be taken into account in the subject Platelet count Decrease \75,000/mm3 Increase C600,000/mm3 with some symptoms, or C1,000,000/mm3 Aspartate aminotransferase (AST) Above 2.5-fold of the upper limit of the institutional standard levels Alanine aminotransferase (ALT) Even if the value is not above 2.5-fold, it should be considered to be handled as an c-Glutamyl transferase (c-GT) adverse event in the following cases: Alkaline phosphatase (ALP)