Living in a SEND World

Two new implementation guides were released in June. How will this impact preclinical safety studies?

Nearly a decade ago, the Clinical Data Interchange Standards Consortium introduced a standard for non-clinical data, known as the Standard for Exchange of Nonclinical Data (SEND), that reflected the massive shift from paper to electronic records. Indeed, SEND offered a way forward for the computerization, electronic application, and screening of animal toxicology data. Soon after the US Food and Drug Administration (FDA) introduced via two Federal Register Notices (FDA-2014-D-0085 and FDA-2012-D-0097), the first ever legally binding guidance documents which mandated the submission of certain data in electronic format.

SEND datasets are an essential component of the review, analysis and interpretation of nonclinical toxicology studies. The SEND datasets are now a requirement for data submitted to the FDA included within an Investigational New Drug (IND) application, New Drug Application (NDA), Abbreviated New Drug Application (ANDA) application and certain Biologic License (BLA) Applications.

But living in a SEND world hasn’t always been easy for sponsors and contract research organizations. Determining which studies require SEND isn’t always a simple Yes or No question. SEND is a complex and difficult scheme that is constantly being updated and clarified. Over the years, updates to SEND have incorporated new data domains for the inclusion of development and reproductive toxicology (DART) embryo-fetal development (EFD), studies. The SEND dataset creation process is a difficult and time-consuming process that involves both data integration and manual efforts to ensure the data is fit for use and compliant.

The most recent iteration of SEND came in June when the CDISC, the global non-profit that actively develops data standards within the pharmaceutical industry, published two new SEND Implementation Guides with accompanying rules for both. One guide focuses on in‑vivo genetic toxicology studies (SENDIG-GeneTox v1.0), and the other on DART (SENDIG-DART v1.2).

What is included in these new guides, and when will these new standards take effect? Here are some of the most perplexing questions labs have about these latest changes to SEND. Do you have a question that isn’t answered here? Please feel free to email it to [email protected].

When will the new implementation guides take effect?

While CDISC has already published the implementation guides, to become required standards for submission, the FDA will issue a Federal Register Notice (FRN) announcing the date support begins for both SENDIG-‑DART v1.2 and SENDIG-‑GeneTox v1.0. Prior to becoming effective, tools will need to be developed for industry and FDA to allow for the creation and the review of these new concepts.

Does the release of SENDIG-Genetox v1.0 mean that all genetic toxicology studies will require SEND?

The SENDIG-GeneTox v1.0 only includes modeling for in vivo micronucleus and comet data. It does not account for any other type of in vitro or in vivo genetic toxicology data. Further data types may be modeled in future releases of the SEND standard.

How does SENDIG-DART v1.2 differ from SENDIG-DART v1.1?

The updated DART implementation guide (IG) was produced, using existing concepts, to add examples for the representation of juvenile animal studies in SEND when reported by post‑natal day rather than study day. Additionally, updates were made to previously published DART domains to address issues resulting from the FDA’s Fit-For-Use pilot of SENDIG-DART v1.1, making SENDIG-DART v1.2 a significant improvement on what was previously published. Specifically, better descriptions on the meaning of study day, dose day, and reproductive phase day were added to clarify certain implementation issues.

Does SENDIG-DART v1.2 bring juvenile studies into scope for SEND?

Section 4.1.3.4.3 of the FDA Study Data Technical Conformance Guide (sdTCG) indicates that single or repeat dose general toxicology studies conducted with juvenile animals currently require SEND.  These studies can be modelled under SENDIG v3.1 and v3.1.1, as these studies are not multi-phase DART studies. These dedicated toxicology studies include postnatal days that can be tied to study days in the nonclinical study data reviewer’s guide (nSDRG).

SENDIG-DART v1.2 adds concepts and examples for juvenile toxicology studies that include reproductive phases and are reported by post-natal day, effectively widening the existing scope of juvenile studies for SEND.

Additional concepts for juvenile studies are still out of scope and will be modelled in a future SENDIG-DART release.

With these two releases, can industry expect SEND standards development to slow down to allow labs time to “catch-up” on implementation?

SEND development will continue to move forward. The CDISC SEND Team is working on a major release, SENDIG v4.0, which is tentatively slated for a 2025 publication. SENDIG v4.0 will include upgrades to general toxicology domains and include new data types, such as immunogenicity specimen assessments, cell phenotyping, nervous system tests, ophthalmic examinations, and irritation assessments. 

Erin Tibbs-Slone is a SEND Senior Specialist with Charles River's Safety Assessment business. Regina Kelder manages the Eureka blog.