FDA Requirements for Providing Datasets for Nonclinical Studies in SEND Format

SEND is evolving with input from sponsors and various stakeholders. The FDA continues to implement data standards for study data by requiring SDTM (Study Data Tabulation Model) and ADaM (Analysis Data Model) standards for clinical data and the SEND standard for nonclinical data. All in-scope clinical and nonclinical studies started on or after requirement dates listed in the FDA Data Standards Catalog must submit data using the specified data standard, or the application may receive a refuse-to-file action. The FDA also checks adherence to the technical rejection criteria at the time of application submission and validation, and will notify the applicant if the submission is rejected.

The Study Data Technical Conformance Guide (TCG) explains the FDA technical rejection criteria (Appendix F).

SEND implementation guides (SENDIG) continue to add domains and study types to the standard. The FDA is strict about rejecting submissions lacking a SEND package that covers all endpoints modeled in the SENDIG for a study, along with a companion data definition file and nonclinical study data reviewer’s guide (nSDRG). The SENDIG notes that the following domains or datasets generally form the foundation of each SEND package: TS, TX, DM, and EX, along with at least one endpoint-related domain dataset (such as BW for body weights). However, the list of domains will be specific to each study and what data were collected.

Below is an example set of files for a simple submission with body weights and clinical observations:

• ts.xpt – Trial Summary (TS) dataset, which provides high-level details about the study. A TS dataset (either full or abbreviated) must be included for each study in specified sections of an electronic Common Technical Document (eCTD) submission, as outlined in the FDA Technical Rejection Criteria, even if the study started before 2016 年 12 月 17 日. In this case, non-clinical legacy data in PDF format should be submitted along with an abbreviated TS dataset. See the section below on Technical Rejection Criteria and Abbreviated TS Domain Requirements for more information.
• ta.xpt – Trial Arms dataset, which specifies the sequence of planned treatment-related events in the study.
• te.xpt – Trial Elements dataset, which lists the treatment-related events in the study, used in the Trial Arms and Subject Elements datasets.
• tx.xpt – Trial Sets dataset, which provides group information.
• dm.xpt – Demographics dataset, which lists the animals in the study.
• ds.xpt – Disposition dataset, which lists the animals along with their disposition status and date.
• se.xpt – Subject Elements dataset, which contains the trial design elements that each subject experienced while participating in the study.
• ex.xpt – Exposure dataset, which provides dosing information.
• bw.xpt – Body Weights dataset, which provides body weight results collected in the study.
• cl.xpt – Clinical Observations dataset, which provides clinical observation results collected in the study.
• nsdrg.pdf -nSDRG (Nonclinical Study Data Reviewer’s Guide), a PDF document that contains information about the datasets that would be helpful to reviewers.
• define.xml – includes metadata about the datasets included in the submission, such as the columns, comments about the columns, data types, Controlled Terminology used, etc.
• define2-1-0.xsl– a static file that allows a visual presentation of the information in the define.xml file when opened with a browser.

The Nonclinical Study Data Reviewers Guide (nSDRG) helps the reader understand the SEND dataset in the context of the study report. The FDA TCG states that the nSDRG is “recommended as an integral part of a standards-compliant study data submission.”While the content and proper format of an nSDRG are not mandated, the FDA has provided some expectations in the TCG, and a template has been developed through the PhUSE Nonclinical Working group.

The define.xml data definition file describes the metadata associated with the datasets for a study. This file is required for SEND submission datasets and follows a separate CDISC standard, Define-XML. The FDA currently requires version V2.1 of the Define-XML standard.

The table below summarizes the FDA SEND data submission requirements by study type, FDA Center, and submission type. The FDA TCG, section 4.1.3.4.1, details and clarifies the scope of SEND as applied to specific study types and study designs, including detailed guidance for embryo-fetal development (EFD) studies, study report status (audited draft or final), GLP (Good Laboratory Practice) status, and more. In general, SEND datasets are required for single dose, repeat dose, carcinogenicity, cardiovascular and respiratory safety pharmacology, and EFD (embryo-fetal development) studies with start dates after the requirement dates listed in the FDA Data Standards Catalog, regardless of GLP or study report status. If it’s unclear whether a given nonclinical study requires SEND datasets, discuss this with the FDA Project Manager for the submission. The animals included in a SEND dataset should be consistent with the animals included in the study report individual animal tables. Generally, this means including pre-test/stock animals if they have been assigned to a test treatment group and have study data collected/reported.

The following table lists nonclinical study types modeled in SEND IGs and associated submission requirement dates by submission type and FDA review division.

*FDA requirement for SEND 3.0 ended 03/15/2019 for NDAs and 03/15/2020 for INDs