Takayuki Anzai

Differences in Rat Models Used in Routine Toxicity Studies

The discussion on whether the Sprague Dawley (SD), the Fischer F344, or the Hannover Wistar rat is the most appropriate model for toxicity studies in rodents is ongoing. A substantial quantity of data on these strains concerning their source, diet, and housing conditions have been published. Generally, before starting a toxicology program in rodents, it should be taken into account that oncogenicity studies will be required for the majority of compounds successfully completing development. Survival, body weight development, incidence, type, time of onset of age-dependent lesions and neoplasms, as well as some special considerations of the rat model selected may be decisive. Therefore, an understanding of the historical background data is essential. These aspects demonstrate why the use of a specific rat model should be carefully considered at the beginning of the toxicology program.

Responses to the Standard for Exchange of Nonclinical Data (SEND) in non-US countries

The Standard for the Exchange of Nonclinical Data (SEND), adopted by the US FDA, is part of a set of regulations and guidances requiring the submission of standardized electronic study data for nonclinical and clinical data submissions. SEND is the nonclinical implementation of SDTM (Study Data Tabulation Model), the standard electronic format for clinical regulatory submissions to FDA. SEND, SDTM, and the associated Controlled Terminology have been developed by CDISC (Clinical Data Interchange Standards Consortium). In order to successfully implement SEND, interdisciplinary contributions between sponsors and CROs, need a model for task allocation. This is being undertaken by the Pharmaceutical Users Software Exchange (PhUSE). Because SEND is currently the preferred submission format of the US FDA only and will become required by it starting in December 2016, only American academic societies and companies are actively involved. An exception to this is the INHAND initiative, which leads the way in standardizing terminology for toxicological pathology. On the other hand, international globalization of other clinical and nonclinical practices is not feasible because there are substantial differences between the US and non-US countries in CRO involvement in drug development. Thus, non-US countries must consider and develop approaches to SEND that meet their needs. This paper summarizes the activities of the major organizations involved in SEND development and implementation, discusses the effective use of SEND, and details a compliance scheme (research material of the Showa University School of Medicine) illustrating how pharmaceutical companies can complete a large amount of work up to an FDA application with the effective utilization of CROs and solution providers.

Specific pathologist responses for Standard for Exchange of Nonclinical Data (SEND)

The Standard for Exchange of Nonclinical Data (SEND), introduced by the US Food and Drug Administration (FDA), is a scheme for the computerization, electronic application, and screening of preclinical data. Since its establishment, related organizations have been working together to implement SEND. However, it is difficult for individual pharmaceutical companies that often outsource to achieve complete compliance with SEND; hence, the cooperation of contract research organizations (CROs) and SEND Registered Solution Providers (RSPs) is indispensable. In SEND, most data, including those on pathology findings, are converted into controlled terminology (CT), but it is not a simple process to convert findings or levels of severity in the field of pathology, which is a descriptive science. The authors have successfully completed an FDA trial submission for a toxicology test conducted at a CRO and in doing so acquired important knowledge. This article presents a clear picture of such important knowledge from a pathologist’s viewpoint.

SEND implementation: Best practices and updates from CDISC and PhUSE

米国FDAが申請データの電子化を推進している背景には、新薬の審査速度の加速が自国の国民にベネフィットが大きいこと、 更に自国の製薬産業の国際優位性を維持する目的がある. 米国はこの政策に成功しており、エール大学の研究グループの調査 によるとFDA、European Medicines Agency (EMA)、カナダ保険庁の3つの行政機関における申請から初回審査終了までの期 間(中央値)の比較(2001年~ 2010年)において、FDAが調査対象機関の中で最短であった. この申請データの電子化の中 で前臨床のデータに関する標準がSEND(Standard for Exchange of Nonclinical Data)である.FDAはCDISC(Clinical Data Interchange Standards Consortium)及びPhUSE(Pharmaceutical Users Software Exchange)とともにその普及に励んでいる. さらにFDAは2012年にIT5カ年計画案を発表し、FDAにおける一連の電子申請および電子審査の推進計画の大綱を示している. また、SENDにおいて考慮すべき点、推奨事項、データセットの提出方法などの細則についてガイダンス案を作成し公開している. FDAはSENDに関し、CDISCとPhUSEとの共同作業を数多く行っているが、 CDISCが標準を作る機関であるのに対し、PhUSE はSENDなどの実装を想定した機関であり、特に製薬企業にとって現実的かつ有益な情報源となっている. PhUSEは製薬企業、 IT企業などのデータ・マネージメント、生物統計、電子臨床データ、毒性、病理、薬理などの専門家によって構成される国際 的非営利団体である. 本発表においてはFDA SENDの現状とPhUSEの活動について紹介しその有効利用を提案する. S3-1 SEND implementation: Best practices and updates from CDISC and PhUSE