Japan Pharmaceutical Manufacturers Association Research Articles

Collaborative work on evaluation of ovarian toxicity by repeated-dose and fertility studies in female rats

The National Institute of Health Sciences (NIHS) and 18 pharmaceutical companies of the Japan Pharmaceutical Manufacturers Association (JPMA) have conducted a validation study intended to evaluate whether a 2-week repeated general toxicity period with histopathological examination is sufficient to detect ovarian toxicity or not. The current repeated dose general toxicity study is considered to be insufficient in terms of evaluating female reproductive function due to a lack of evidence indicating that it is adequate. Evaluation of ovarian toxicity by comprehensive histopathological examination of the female reproductive organs based on the underlying morphology of a normal cycle of the reproductive tract including the ovary and additional immunohistochemical staining with proliferative cell nuclear antigen (PCNA) to identify small follicles may be a good tool to assess female reproductive function. In the collaborative study, 2- or 4-week repeated dose toxicity studies with ovarian histopathological examinations were conducted. A female fertility study was also conducted to compare the results with those of the ovarian histopathological findings. A total of 17 test substances were evaluated and categorized into hormone analogues, primordial follicle damaging agents, metabolite imbalance inducers, and endocrine imbalance inducers. Based on the results, ovarian toxicity could be detected by a careful histopatholgical examination. A 2-week dosing period may be sufficient for the evaluation of ovarian toxicity, except for cytotoxic compounds such as alkylating agents. The pathological findings of ovarian toxicity (decreases in follicles, increases in atretic follicles, increases in currently formed corpora lutea, etc) reflected the female fertility parameters (irregular estrous cycle, pre-implantation loss).

個別症例安全性報告の因果関係評価基準の問題点

The purpose of this study was to clarify the causality assessment information items necessary to improve the usefulness of individual case safety reports (ICSRs) from medical facilities as adverse drug reaction (ADR) information.To do this,we investigated standard causality assessment items used by pharmaceutical companies.The number of the companies responding was 76,93.8% of all Japan Pharmaceutical Manufacturers Association (JPMA) member companies.We found that the use of algorithms for causality assessment,the grades and expressions used to describe causality,and criteria for determining whether reactions were ADRs or not varied among the companies as well as their divisions (whether they conducted clinical trials or post-marketing surveillance).Having such a variety of assessment criteria is inconvenient for the reporters who have to judge it and also lowers the validity of judgments.It also hampers the overall assessment of ADR information and may cause great differences in ADR frequencies.We therefore feel that it is desirable to agree on international criteria for causality assessment as soon as possible.

非臨床安全性研究担当者の教育に関するアンケート調査報告（１）：日本の製薬企業における教育の現状 - 日本製薬工業協会 基礎研究部会 教育タスクフォース -

非臨床安全性研究担当者の教育に関するアンケート調査報告（１）：日本の製薬企業における教育の現状 - 日本製薬工業協会 基礎研究部会 教育タスクフォース -

非臨床安全性研究担当者の教育に関するアンケート調査報告（２）：安全性試験実務者の教育 -日本製薬工業協会 基礎研究部会 教育タスクフォース-

非臨床安全性研究担当者の教育に関するアンケート調査報告（２）：安全性試験実務者の教育 -日本製薬工業協会 基礎研究部会 教育タスクフォース-

非臨床安全性研究担当者の教育に関するアンケート調査報告（３）：総合的安全性評価者の育成 - 日本製薬工業協会 基礎研究部会 教育タスクフォース -

非臨床安全性研究担当者の教育に関するアンケート調査報告（３）：総合的安全性評価者の育成 - 日本製薬工業協会 基礎研究部会 教育タスクフォース -

ワクチンの非臨床安全性評価に関する検討 _-_日本製薬工業協会 基礎研究部会 ワクチンの非臨床安全性試験ガイドラインタスクフォース_-_

ワクチンの非臨床安全性評価に関する検討 _-_日本製薬工業協会 基礎研究部会 ワクチンの非臨床安全性試験ガイドラインタスクフォース_-_

蛋白質構造解析コンソーシアムの創薬産業ビームライン

The Pharmaceutical Industry Beamline was constructed by the Pharmaceutical Consortium for Protein Structure Analysis which was established in April 2001. The consortium is composed of 22 pharmaceutical companies affiliating with the Japan Pharmaceutical Manufacturers Association. The beamline is the first exclusive one that is owned by pharmaceutical enterprises at SPring-8. The specification and equipments of the Pharmaceutical Industry Beamline is almost same as that of RIKEN Structural Genomics Beamline I & II.

Guidance on Drug Interaction Studies: From the Aspect of Drug Development.

The mechanisms of drug interactions are divided into pharmacokinetic interactions and other interactions (pharmacodynamics etc). The Japanese Guidance on Drug Interaction Studies (draft), which was presented in April 2000 mainly refers to pharmacokinetic interactions and extensively covers all stages of drug development, including non-clinical, clinical, and post-marketing studies. On the other hand, drug interaction guidances have already been introduced in other regions in the world, and there are significant differences between Japan and other regions. Therefore, there is a need for worldwide harmonization (such as having it adopted as a topic of the ICH). Taking the above background into account, the Pre-Clinical Evaluation Subcommittee of the Drug Evaluation Committee of the JPMA (Japan Pharmaceutical Manufacturers Association) established a working group in the fourth division (responsible for ADME) to coordinate opinions of the pharmaceutical companies in cooperation with Clinical Evaluation Subcommittee. At the same time, we compared the Japanese draft guidance with the guidances of other regions and have already submitted the results to the regulatory authorities through the Japan Federation of Pharmaceutical Organizations (NICHIYAKUREN). This article discusses the issues that may be encountered in the actual process of interaction evaluation and differences from other regions impacting international harmonization.

Drug Interaction Working Group. Japan Pharmaceutical Manufacturers Association.

In current clinical practice, concomitant multiple drug administration regimens involving the simultaneous use of two or more kinds of drugs are extensively applied. To ensure the proper use of the drug and their safety, drug-drug interaction is a critically important factor. This issue also has aroused great social interest in view of the well-known sorivudin event. The majority of adverse drug-drug interactions are due to pharmacokinetic interactions, and around three quarters of these are associated with drug metabolism. Most of the interactions occurred as results of inhibition or induction to metabolic enzymes are clinically significant. The FDA of the U. S. A. and the CPMP of the E. U. have successively published drug-drug interaction guidance in 1997. In Japan, the guideline/guidance for drug-drug interaction is under discussion. Our JPMA focused on the theme of drug-drug interaction and established a working group in May 1997 to study drug-drug interaction, with dedicated efforts being made to prepare a database on drug-drug interaction. It is the very important mission for pharmaceutical manufacturers to provide pharmacokinetic/pharmacodynamic information of drugs for safe use. In July 1998, JPMA member companies were requested to complete questionnaires. The inquiry has elicited a roughly 80% response on 65 drugs until the present. We will persevere in our task to establish a database that will be of real practical value, on the basis of the most helpfull data provided by the companies concerned. We would also like to refer to our future plan adding the background and results of the activities that are being carried out.

製薬業界でのＭＳ分析と精度管理

The quality control of the data and instruments on the analysis of drugs by mass spectrometry should be controlled by analytical section of pharmaceutical company. ICH, FDA, EMEA, and Ministry of Health and Welfare guidelines related the criteria of quality control of analytical method have been published. The purity and stability of the drugs are analyzed according to Validation of Analytical Procedures (ICH, 1994.10). The clinical pharmacokinetics samples are analyzed according to Guidance for Industry; Bioanalytical Methods Validation for Human Studies (FDA, 1998.12). Toxicokinetics samples are analyzed according to Validation of Analytical Procedures for toxicokinetics (Japan Pharmaceutical Manufacturers Association (JPMA), 1997.3). In this report, I write the actual quality control of analytical instrument and procedure by mass spectrometry in the pharmaceutical companies and compare the above described guideline.

Overview of the Fourth International Conference on Harmonization

This overview of the Fourth International Conference on Harmonization (ICH 4), held in Brussels, Belgium, 16-18 July 1997, summarizes results and provides information regarding the nonclinical workshop and issued nonclinical testing guidelines [Draft Final (Step 4) Guidelines recommended for adoption to the regulatory bodies of the EU, Japan, and the USA]. ICH 4 completed the initial harmonization targets for the three ICH Regions [European Commission-European Union (EU) and European Federation of Pharmaceutical Industries' Association (EFPIA); Ministry of Health and Welfare (MHW) Japan and Japan Pharmaceutical Manufacturers Association (JPMA); and the U.S. Food and Drug Administration (FDA) and Pharmaceutical Research and Manufacturers of America (PhRMA)] and the International Federation of Pharmaceutical Manufacturers Associations (IFPMA). Proceedings will be available in book form. Earlier conferences, guidelines, and proceedings are available on CD-ROM and in print and diskette form from the ICH Secretariat, c/o IFPMA, 3 rue de St.-Jean, P.O. Box 9, 1211 Geneva 18, Switzerland; Tel +41 (22) 340 12 00; Fax +41 (22) 345 82 75. Similar information is obtainable from the ICH Home Page (http://www.ifpma.org/ich1.html) and the Pharm Web home page (http://www.pharmweb.net).

The Practice of Preclinical Immunotoxicity Testing in Japan

In Japan, data on indirect immunotoxicity tests but not direct immunotoxicity tests are required for new drug applications. Antigenicity studies among indirect immunotoxicity tests are conducted on a case-by-case basis and empirically evaluated by acute systemic anaphylaxis and passive cutaneous anaphylaxis reactions in guinea pigs. The remaining skin sensitization and skin photosensitization studies are regulated by guidelines for dermatological preparations. Respecting direct immunotoxicity tests, a Japan Pharmaceutical Manufacturers Association (JPMA) questionnaire made it clear that some pharmaceutical companies have established the testing capabilities in their laboratories. In this paper, the practice of preclinical immunotoxicity testing in Japan is presented in comparison with those of the United States and the European Union.

Japan Pharmaceutical Manufacturers Association (JPMA) Survey on Background Control Data of Developmental and Reproductive Toxicity Studies in Rats, Rabbits and Mice

ABSTRACT The Non‐Clinical Evaluation Subcommittee of the Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA) collected historical control data from developmental and reproductive toxicity studies, which were conducted by the member companies and associated contract laboratories between 1986 and 1993. The data include spontaneous incidences of fetal morphological alterations and other observations made at terminal cesarean sections in rats, rabbits and mice. In addition, mating and natural delivery data in rats are also provided. There were strain differences as well as inter‐laboratory variations in the incidences of fetal visceral and skeletal alterations for both rats and rabbits. These inter‐laboratory variations were attributed to differences in the selection of observation parameters, observation criteria and classification of the findings.

Current status of conducting function tests in repeated dose toxicity studies in Japan.

It seems desirable to conduct as many function tests as possible in repeated dose toxicity studies, but is it practicable? The current status of conducting function tests in repeated dose toxicity studies in Japan was investigated by a literature survey of more than one thousand papers published in seven Japanese toxicology journals during the past 10 years and by a questionnaire survey directed to toxicologists among the Japan Pharmaceutical Manufacturers Association (JPMA) member companies. The function tests often carried out in repeated dose toxicity studies were, for example: 1) electro-retinography (ERG) and visually evoked potential (VEP) for visual test and tonometer for intraocular pressure; 2) auricular reflex, evoked response audiometry (ERA) and auditory brainstem response (ABR) to sound stimuli; 3) respiration and heart rate, electrocardiogram (ECG) and blood pressure by noninvasive cuff methods or using electronic devices such as telemetry; 4) body temperature, spontaneous motility and some adaptation tests (using rotarod and sloped plate in rats); 5) indocyanin (ICG) or bromosulfophtalein (BSP) for hepatic test; 6) phenolsulfonphtalein (PSP) and creatinine clearance for renal test; and 7) immunoglobulin, leukocyte phagocytosis, lymphocyte blastgenesis and natural killer cell (NK) for immuno-reaction test. Limitations to conducting function tests in repeated dose toxicity studies and issues to be resolved were discussed, based on questions and suggestions given by the respondents to the questionnaire. Although it certainly seemed desirable to conduct as many function tests as possible in repeated dose toxicity studies, most of the function tests so far introduced into toxicity studies were not satisfactory, because those tests could not be carried out under the restricted conditions of repeated dose toxicity studies, and not much reliable data from function tests were obtainable. A variety of function tests should firstly be incorporated into single dose toxicity studies together with development of a new concept for methodology in safety pharmacology.

Clinical pathology reference ranges of laboratory animals. Working Group II, Nonclinical Safety Evaluation Subcommittee of the Japan Pharmaceutical Manufacturers Association.

We analyzed historical control data of clinical pathology testings provided by sixty-seven member companies of the Japan Pharmaceutical Manufacturers Association covering study populations of approximately 7,000 rats/sex, 5,000 dogs/sex, and 700 monkeys/sex. This paper assesses the relationship between conditions of sample collection, methods of measurement, etc. and potential factors contributing to variations in reference data, based on weighted means and standard deviations thereof derived from data for rats, dogs and monkeys for those parameters measured using methods most common to the participating facilities. Parameters included erythrocyte count (RBC), hematocrit (Ht), hemoglobin concentration(Hb), reticulocyte count (Rt), platelet count, total leukocyte count (WBC), differential leukocyte count (%WBC), coagulation time (activated partial thromboplastin time: APTT, prothrombin time: PT), and serum/plasma levels of GOT, GPT, ALP, LDH, glucose, cholesterol, triglycerides (TG), total protein, albumin, urea nitrogen (UN), creatinine, sodium (Na), potassium (K), calcium (Ca), chloride (Cl), inorganic phosphorus (Ip), and CPK. Analyses of the data revealed species differences in RBC, Ht, Rt, platelet count, WBC, %WBC, ALP, LDH, glucose, cholesterol, TG, total protein, UN, creatinine, Ca, Ip, and CPK. There were strain differences in rats in platelet count, WBC, GOT, ALP, UN, creatinine, and CPK. Sex differences were noted for Hb, Ht, WBC, ALP, glucose, cholesterol, TG, total protein, A/G ratio, UN, and Ip. Age differences were observed with RBC, Hb, Ht, Rt, %WBC, GOT, GPT, ALP, LDH, cholesterol, TG total protein, Ip, and CPK. APTT, PT, ALP, glucose, TG and UN were found to be subject to the influence of fasting/feeding. In rats, Ht, WBC, CPK and K showed differences by the site of bleeding. Observed values for LDH and CPK varied with specimen type, plasma or serum; serum assay values showed greater variation than plasma values.

Spontaneous Malformations in Laboratory Animals: Frequency of External, Internal and Skeletal Malformations in Rats, Rabbits and Mice*

Congenital AnomaliesVolume 27, Issue 2 p. 147-206 Free Access Spontaneous Malformations in Laboratory Animals: Frequency of External, Internal and Skeletal Malformations in Rats, Rabbits and Mice* Haruka MORITA, Haruka MORITA A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanSearch for more papers by this authorFumio ARIYUKI, Fumio ARIYUKI A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanSearch for more papers by this authorNorikazu INOMATA, Norikazu INOMATA A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanSearch for more papers by this authorKoichi NISHIMURA, Koichi NISHIMURA A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanSearch for more papers by this authorYasuhiko HASEGAWA, Yasuhiko HASEGAWA A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanSearch for more papers by this authorMasaki MIYAMOTO, Masaki MIYAMOTO A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanSearch for more papers by this authorToshiki WATANABE, Corresponding Author Toshiki WATANABE A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanDrug Safety Research Center, Daiichi Seiyaku Co., Ltd., 16-13 Kita-kasai 1-Chome, Edogawa-ku, Tokyo 134, JapanSearch for more papers by this author Haruka MORITA, Haruka MORITA A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanSearch for more papers by this authorFumio ARIYUKI, Fumio ARIYUKI A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanSearch for more papers by this authorNorikazu INOMATA, Norikazu INOMATA A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanSearch for more papers by this authorKoichi NISHIMURA, Koichi NISHIMURA A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanSearch for more papers by this authorYasuhiko HASEGAWA, Yasuhiko HASEGAWA A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanSearch for more papers by this authorMasaki MIYAMOTO, Masaki MIYAMOTO A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanSearch for more papers by this authorToshiki WATANABE, Corresponding Author Toshiki WATANABE A Team for the Investigation of the Spontaneous Malformations in Laboratory Animals, Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), Hon-cho, Nihonbashi, Chuo-ku, Tokyo 103, JapanDrug Safety Research Center, Daiichi Seiyaku Co., Ltd., 16-13 Kita-kasai 1-Chome, Edogawa-ku, Tokyo 134, JapanSearch for more papers by this author First published: June 1987 https://doi.org/10.1111/j.1741-4520.1987.tb00703.xCitations: 70 † *This paper is a publication commemorative of the 25th anniversary (1985) of the Japanese Teratology Society. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume27, Issue2June 1987Pages 147-206 RelatedInformation