The Standard for Exchange of Nonclinical Data (SEND) is a standardized, electronic format for exchanging nonclinical data related to drug development. SEND was developed by the Clinical Data Interchange Standards Consortium (CDISC), a globally recognized, not-for-profit organization that develops data standards with the input of pharmaceutical industry experts. The FDA requires drug developers to use the SEND standard because this consistent format allows regulatory agencies to streamline the review of the nonclinical sections of drug submissions.
Sponsors may struggle when navigating SEND data standards regulations because of a lack of knowledge of the requirements. In this blog, I’ll discuss the updates to the Standard for Exchange of Nonclinical Data (SEND) and other data standards for 2023 that you should be aware of which include:
- changes in version 3.1.1 of SEND,
- the introduction of requirements for SEND submissions to CBER,
- expansion of the requirements for SEND IG version 1 for Animal Rule,
- the introduction of requirements for SENDIG version 1.1 for Developmental and Reproductive Toxicology (DART) studies, and
- the requirement for the latest version of the Define-XML standard (Version 2.1)
- upcoming changes for SEND version 4.0, scheduled for publication by CDISC in April 2025.
For a deeper dive into this topic, check out this webinar “What’s New for SEND 2023.”
New SEND Requirements for 2023
As of 3/15/2023, there were several standard version requirement changes published in the FDA Data Standards Catalog that are related to SEND and nonclinical data and submissions.
- SEND Implementation Guide 3.1.1, the latest version of the SEND standard, is now required for studies with start dates after 3/15/2023.
- SEND 3.1 or SEND 3.1.1 datasets are required for submissions to the FDA Center for Biologics Evaluation and Research (CBER) for studies starting after 3/15/2023. Previously only FDA Center for Drug Evaluation and Research (CDER) submissions required SEND datasets.
- SEND Implementation Guide for Animal Rule V1.0 is required for Investigational New Drug (IND) submissions for studies starting after 3/15/2023. The requirement for this standard for studies included in NDA submissions started last March.
- SEND Implementation Guide for Developmental and Reproductive Toxicology studies (DART) V1.1 is required for embryo-fetal development (EFD) studies starting after 3/15/2023 that are included in NDA submissions. The requirement for IND submissions for SENDIG-DART V1.1 will take effect next March.
- V2.1 of the define.xml standard is required for studies starting after 3/15/2023. Define.xml files are required as part of all SEND dataset submission packages.
Of note, both SEND 3.1.1 and define.xml 2.1 are now required for studies starting after 3/15/2023, but because support and requirement end dates haven’t been published for the prior versions of the SEND or define standards in the FDA Data Standards Catalog, either SEND 3.1 or SEND 3.1.1 or define 2.0 or define 2.1 are acceptable, although the latest versions of the standards are preferred.
SEND V3.1.1
SEND IG Version 3.1.1 was originally released in March of 2021 and primarily covers changes to the Pharmacokinetic Concentration and Pharmacokinetic Parameter domains (PC and PP domains) to ensure that creation of time/concentration curves could be done by FDA using the data from these two domains.
To support this, there are changes to variable permissibility, assumptions, and examples (including cross domain examples) to make it clear what data is expected to be populated for the data to be used as intended. Most notably, the PCELTM and PCTPTREF variables were changes to Expected rather than Permissible and PCDTC was changed from Expected to Permissible. In addition, the unscheduled flag variable was added to the PC domain to support flagging of unscheduled results.
SEND for CBER
Until this year, the SEND data requirements only applied to CDER submissions. As of March 15, 2023, the SEND standard also applies to CBER submissions.
The study and data types included for CBER are the same as for CDER, except for the requirement for SENDIG-DART v1.1 for embryo-fetal development studies, which is not required for CBER. In-scope study types for CBER include single, repeat dose, carcinogenicity, and cardiovascular and respiratory safety pharmacology studies. The data types required are those modeled in CoDEx V1.0 for SEND V3.1.
FDA has included information in the Technical Conformance Guide specifically related to the handling of immune response data for CBER submissions in SEND 3.1 or SEND 3.1.1, as it is not modeled in this version of the SEND IG but will be included in the next version as the Immunogenicity Specimen Assessments (IS) domain is planned to be included in SEND V4.0. In the meantime, CBER prefers that immune response data be included in either the LB domain or in the IS domain as a custom domain for SEND 3.1/SEND 3.1.1. Custom domains are supported starting with SEND v.3.1. Alternatively, per the FDA Technical Conformance guide, it is also acceptable for immune response data to only be submitted as part of the tables included in the study report.
SENDIG-AR V1.0
SEND Implementation Guide for Animal Rule V.1.0 (SENDIG-AR V1.0) became a requirement last year for studies starting after 3/15/2022 included in NDA submissions. As of 3/15/2023, the requirement is now extended to IND submissions as well.
Studies submitted under the Animal Rule differ from general toxicology studies in that the Animal Rule applies to using adequate and well-controlled studies in animal models rather than in humans for situations where conducting clinical trials in humans is unethical. These conditions are life-threatening and related to exposure to lethal or permanently disabling toxic chemical, biological, radiological, or nuclear substances. While typical toxicology studies submitted as part of NDA or IND applications focus on testing the toxic effects of treatments, Animal Rule studies focus on the natural history of diseases and testing treatment safety and efficacy in animal models.
SENDIG-AR V1.0 introduces several new domains and variables to the SEND model as well as updates for SEND-controlled terminology.
SENDIG-DART v1.1
Embryo-fetal development studies started after 3/15/2023 submitted in NDA applications to CDER will now require SEND datasets. The requirement for INDs will take effect next March.
Embryo-fetal development studies are modeled in the SEND implementation guide for Developmental and Reproduction Toxicology V1.1 (SEND-IG DART V1.1). This IG contains new domains for pregnancy and fetal findings, new timing variables to track results relative to gestation start and significant additions to SEND controlled terminology requirements.
FDA Technical Rejection Criteria is not currently implemented for eCTD module 4.2.3.5.2, which is where Embryo-Fetal Development studies are located. So simplified ts.xpt domains do not need to be submitted to indicate SEND datasets are not required for a study. If you do submit a simplified ts.xpt domain in this eCTD module, the FDA has confirmed that it will not interfere or prevent electronic receipt or validation.
The FDA has also provided clarification on requirements for SEND-IG DART V.1.1. in the Technical Conformance Guide. The clarifications are helpful in determining specific SEND requirements for common development scenarios.
Define.xml V2.1
Define.xml V2.1 is now an FDA requirement for studies starting after 3/15/2023. This latest version of define.xml is like V2.0, with notable changes listed above.
- More than one data standard can be referenced, using the new def:Standards element. Thus, for SEND studies where you may be using SEND V3.1 for most domains but SDTM for a custom domain, both standards can be referenced.
- Introduction of SubClass, which allows programmers to provide a more descriptive classification of their datasets. As of today, the only defined use cases for this concept exist for Analysis Data Model (ADaM) submissions.
- New method for identifying empty datasets and variables with no values. This is flagged with a new attribute called def:HasNoData on both the ItemGroupDef element (for datasets) and the ItemRef element (for variables).
- ORIGINs were also enhanced to include both Type and Source (although for SEND datasets, only ORIGIN Type is used).
A full list of changes in Define 2.1 is included in the Define 2.1 specification, available from the CDISC website.
SEND 2024 and Beyond
There are already two changes on the horizon related to Developmental and Reproductive Toxicology. First, SEND-IG DART v1.1 will be required for studies starting after 3/15/2024 that are included in IND submissions. In addition, SENDIG-DART V1.2 was released in June 2023 and includes modeling and examples for general toxicology studies conducted on juvenile animals, as well as the addition of the Developmental Milestones (DP) domain. It’s unknown when this updated version of the DART IG will be supported or required by FDA, but when that does happen, it will be posted in the FDA Data Standards Catalog.
When we look ahead for SEND, the biggest change coming is related to the finalization and implementation of the next major version of SEND, V4.0. This version is still in development with CDISC but is currently projected to reach the public review stage in the 3rd quarter of 2024.
SEND V4.0 has significant changes, including the addition of eight new domains covering in-vivo genetic toxicology, cell phenotyping, immunogenicity, ophthalmology examinations, pharmacokinetic inputs, nervous system test results, skin test results, and scoring scales. Additional changes planned to the existing standard include an update of the Microscopic Findings (MI) domain to include targeted staining, sexual maturity, and reproductive cycle results, new variables for result modifiers, category/subcategory, and time to detection as well as depreciation of the Tumor Findings (TF) domain.
At this point, CDISC’s final publication date for SEND 4.0 is planned for April 2025, although this could change based on feedback from the public review comments and other factors. For more information regarding SEND 4.0 or to get involved in the development and finalization of this standard, visit the CDISC SEND website.
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