SEND Updates and Technical Rejection Criteria

Hello everyone and welcome to our presentation, SEND Updates and Technical Rejection Criteria. Presenting the session today is Audrey Walker who is the Senior Director and SEND practice lead here at Charles River. I'll now pass it over to Audrey to begin the presentation.

Thank you, Katie, for the introduction, and thank you all for attending my session today. The topics I will discuss today are FDA requirements and CDISC SEND Implementation Guides, future requirements, the FDA Technical Rejection Criteria, also known as the TRC, and New SEND scope within the FDA study data Technical Conformance Guide, also known as the TCG.

The FDA requirements and CDISC SEND Implementation Guides. What is CDISC SEND? CDISC stands for the Clinical Data Interchange Standards Consortium. This consortium is mixed up of volunteers from pharmaceutical companies, CROs, vendors, and FDA. We all volunteer our time to create the standards. SEND stands for the standard for exchange of non-clinical data. SEND is the industry standard for the content, the data, the terminology and the structure of variables for non-clinical data submitted to the FDA, a standard format that enables the efficient exchange of data between organizations and makes it possible to design tools for visualization and storage of data.

It enables an efficient review of non-clinical tox data. The US FDA is the only regulatory agency that requires SEND. The Center for Drug Evaluation and Research is the only division currently requiring SEND datasets. The Center for Biologic Evaluation and Research has mandated SEND for studies that start in 2023. Japan's PMDA is still evaluating the use of SEND.

What is the SENDIG, standard for exchange of non-clinical data Implementation Guide? The SENDIG is based on the CDISC Study Data Tabulation Model, known as the SDTM, for clinical data. The SENDIG is the Implementation Guide that contains the specifications for SEND implementation. There are five published SENDIGS, SENDIG version 3.0, SENDIG version 3.1, SENDIG-DART version 1.1, SENDIG-AR version 1.0, and SENDIG version 3.1.1. The study start date and the study design will determine which SENDIG is required. The scope and requirement dates of the SENDIGS. SEND is required for both GLP and non-GLP studies submitted to FDA Center for Drug Evaluation and Research. The scope of SENDIG 3.0 is single dose toxicity, repeat dose toxicity, and carcinogenicity studies that started protocol signature date on December 17th, 2016.

The scope of SENDIG 3.1 is single dose toxicity, repeat dose toxicity, and carcinogenicity studies, as well as safety pharm cardiovascular, and safety pharm respiratory studies that started protocol signature date, again, March 15th, 2019. The scope of the SENDIG-AR version 1.0, which is annual rule studies, challenge agent studies, studies that started March 15th, 2022. And the defined file that accompanies the SEND datasets is for Define 2.0. FDA requirements and CDISC Implementation Guides.

Where can I get this important information? Well, to start with, the FDA Study Data Standards resource page is a great place to start. You can find documents like the FDA Data Standards Catalog. This can be downloaded. This document indicates the standard that are required along with the requirements start dates and end dates. FDA guidance documents, technical guides such as the Study Data Technical Conformance Guide, known as the TCG. You can also find the FDA business and validation rules, FDA CDER and CBER contact information can also be found on that page. Another great resource on the FDA's web page is the Electronic Common Technical Document known as the eCTD. The eCTD Guidance, along with the Technical Rejection Criteria (TRC) for the Study Data and eCTD Validation Criteria is also available on the FDA's web page.

Another resourceful FDA website is the Study Data for Submissions to CDER and CBER. On this page, you'll find the Technical Rejection Criteria for Study Data, the Technical Rejection Criteria Self-Check Worksheet, the worksheet instructions, and a video on how to use the Self-Check Worksheet. There is also a guide on how to create the simplified TS. The CDISC website is a great place for other resources. It contains all SDTM model versions, all SEND Implementation Guides, the current SEND Conformance Rules, all Confirmed Data Endpoints for Exchange known as CoDEx, the Knowledge Base, and archived Conformance Rules.

On the CDISC website, there's great information about how the IGs are linked. So how the SDTM is linked to the SENDIG, which is linked to Conformance Rules and the CoDEx. As an example, the SEND 3.0 is linked to SDTM 1.2, and it has linked to SEND Conformance Rules version 4.0, and it's linked to the CoDEx 3.0. Another great resource on the CDISC webpage is a CDISC SEND Controlled Terminology, also known as CT. You can find all versions of CT including SEND, CT release information, the NCI FTP links to download the CT, and resources such as new term request page, multiple term requests, CT requests denied, and the publication schedule. The next topic we're going to discuss are future requirements.

Their requirements to the Center of Drug Evaluation and Research are as follows. The SENDIG-DART version 1.1 includes reproductive and development toxicology, only embryo-fetal development. The requirements start March 15th, 2023. That's protocol signature date. For SENDIG 3.1.1, the scope is single dose toxicity studies, repeat dose toxicity, carcinogenicity and respiratory safety pharm studies, cardiovascular safety pharm studies all with the same start date as March 15th, 2023. Submissions to the Center for Biologics and Research start March 15, 2023 as well for SENDIG 3.1 and 3.1.1. The scope of those are also single dose tox, repeat dose tox, carcinogenicity, and respiratory and cardiovascular studies. Define 2.0 should be used for any study that started December 17th, 2016 and on that is submitted to CDER. Studies that start March 15th, 2023 submitted to CDER or CBER must use Define 2.1.

The future of SEND. SEND Implementation Guides in development. We have DART version 1.2, which includes juvenile toxicology studies. We have the SENDIG-GT version 1.0, which is genetic toxicology studies in vivo only. We have the SENDIG version 3.2, which includes upgrades to general tox, additions such as immunotoxicology, cell phenotyping, and anti-drug antibody, the IS and CP domains. SENDIG-DO version one includes dermal ocular irritation studies, and SENDIG-SP version 1.0 includes safety pharmacology studies including CNS testing. This slide depicts the CDISC SEND team release schedule. This is a proposed schedule. It includes all our deliverables and the internal review dates and the lock for publication dates. As you can see, as an example, gene tox is expected to have internal review for Q2 2022 and be locked for publication Q1 2023. The dermal ocular IG version 1.0 is expected to be released 2025 for internal review and locked for publication by Q4 2025 The FDA Technical Rejection Criteria, known as the TRC.

The United States food and Drug Administration recently published the effective dates for the Electronic Common Technical Document, the Technical Rejection Criteria for Study Data, along with the eCTD validation criteria. What does this mean for non-clinical data submitted? Beginning September 15th, 2021, the FDA implemented eCTD validation checks for study information submitted within certain sections of the module in eCTD. Submissions that fail the Validation Criteria will be subject to rejection. So Charles River encourages sponsors to review all the materials related to the eCTD Technical Rejection Criteria as soon as possible to ensure your submission does not get rejected. If you have any questions, we are here for you. Read the full story on the Charles River website.

The FDA Technical Rejection Criteria checks the current scope industry has implemented. So if you place studies in the eCTD folder 4.2.3.1 single dose toxicity, 4.2.3.2 repeat dose toxicity, or 4.2.3.4 carcinogenicity, the Technical Rejection Criteria applies. If you place studies in section 4.2.1.3 respiratory and cardiovascular, SEND is still mandated, but the Technical Rejection Criteria is not on yet. Note, SEND is not required for study types not listed in the FDA supported SENDIG even if some of the endpoints are able to be modeled in SEND. An example of this is primary pharmacology. Yes, there are some endpoints that are modeled in SEND, but primary pharmacology is out of scope. The scope of SEND study data requirements are as follows for studies submitted to CDER. Studies that started December 17th, 2016, again, protocol signature date, NDAs, ANDAs, and BLAs are required.

Studies that started December 17th, 2017, again, protocol signature date, commercial INDs are required. Any non-clinical study information filed in the eCTD module sections 4.2.3.1, 4.2.3.2, and 4.2.3.4, must meet the minimum standards. If the study was conducted before the requirement dates, a simplified TS is required. CRL can provide that simplified TS for additional fee. The simplified TS contains a start date, or if the study is not applicable. If the study was conducted after the requirement dates, a fully compliant SEND dataset package is required including, but not limited to, the TS, the DM, and the Define file. SEND Technical Rejection Criteria checks apply to module four. Again, the sections that are being checked are 4.2.3.1 single dose toxicity, 4.2.3.2 repeat dose toxicity, and 4.2.3.4 carcinogenicity. The checklist for SEND dataset success is the following.

STUDYID in the Study Tagging File matches the STUDYID or sponsors reference ID in the TS file. The dataset named TS that contains the study start date is present for each study. The correct Study Tagging Files are used for all standardized datasets and corresponding Define XML documents. A demographics dataset and Define XML are submitted for each study in module 4.2.3.1, 4.2.3.2, and 4.2.3.4. And lastly, a Study Tagging File is submitted for each study in module 4.2.3.1, 4.2.3.2, and 4.2.3.4. Technical Rejection Criteria Study Tagging File and Sponsor Reference ID. As stated before, the technical checks went into effect September 15th, 2021.

Action is required if your Charles River study is going to be included in a submission to CDER, your Charles River study is a single dose toxicity study, repeat those toxicity study, or carcinogenicity study filed in section 4.2.3.1, 4.2.3.2, or 4.2.3.4 respectively. You are not using the Charles River study number as the reference identifier. And either of the following statements is applicable. The sponsor reference number in the Charles River study protocol is different from the reference identifier used to identify the study in the submission in your study tagging file. You did not provide the sponsor reference number in the study protocol. Please contact Charles river. No further action is needed if your Charles river study is not going to be submitted to CDER for submissions.

Your Charles River study is going to be included in a CDER submission, but not in those folders, single dose tox, repeat dose tox, or carcinogenicity. Charles River study number is the reference identifier that will be used to identify the studies in the submission in the study tagging file, or the sponsor's reference number included in Charles River study protocol is the reference identifier that will be used to identify the study and the submission in the study tagging file. The new SEND scope within the FDA Study Data Technical Conformance Guide. So as previously stated, the technical conformance checks are run in 4.2.3.1, 4.2.3.2, and 4.2.3.4. No other eCTD folder has conformance checks run against them. Is there ambiguity in the SEND scope? Although the SENDIG contains a statement regarding the scope of SEND, there is variability in these study designs that leads to different interpretations of which study requires SEND datasets. To address this ambiguity, the FDA added information to the TCG to clarify FDA expectations for SEND.

This is a quote from the FDA TCG. It is acknowledged that some of these study types can encompass a broad range of study designs, example, number of animals per group, number of endpoints tested, and have difference drug development purposes, example, exploratory or tolerability studies versus standard toxicity studies designed to assess clinical safety. This is from the FDA Technical Conformance Guide. The FDA's TCG has added further SEND scope clarification. Studies that support the safety of proposed clinical trial under commercial IND development, support of marketing authorization, support of product labeling. These non-clinical studies identify potential safety concerns, support the dose and duration of human clinical trials, characterize the toxicologic profile of the test article and proposed clinical product. These study designs incorporate endpoints that can identify non-clinical target organ toxicity, dose or exposure dependency.

Further SEND scope clarification report types. Study report status does not impact the SEND requirement when a draft interim or final report is submitted to the FDA and associated SEND dataset package based on that version of the report must also be submitted if SEND is required for that study. So if you are going to submit a draft, an associated SEND package is needed. If you're going to submit an interim report, an associated SEND packages needed. And if you're going to submit a final report, an associated SEND package is needed. GLP status. SEND is required for both GLP and non-GLP studies. Both GLP and non-GLP studies may be submitted to the FDA to support clinical safety.

So the decision to include SEND is independent of GLP status. Animal age does not impact the SEND requirement. General toxicology studies conducted in juvenile animals, young post weaning animals require SEND. Dedicated multi-phase juvenile studies do not require SEND. Special protocol assessments, also known SPAs. Carcinogenicity and repeat dose toxicity studies that support a carcinogenicity special protocol assessment require SEND if those studies were started on or after the FDA supported SENDIG requirement date in the FDA data standards catalog. These studies are used to inform regulatory decisions related to the risk to human subjects and ultimately impact product labeling.

The last clarification in the TCG is drug substance. The SEND requirement is not based on the drug substance being evaluated. A non-clinical study that is conducted to assess the safety of any component or metabolite of the proposed clinical therapeutic product may require SEND. This includes active moiety, API, impurities, excipients, leachables, extractables, pro-drugs, combination products, vaccine adjuvants, and drug device combinations. The references on this slide can be found on the FDA study data standards resource page, the FDA's electronic common technical document page, the FDA's study data for submission to CEDR and CBER page, the CDISC SEND webpage, and the CDISC Wiki. Thank you for attending this session. If you have any further questions, please feel free to contact me, Audrey Walker, or your client service rep. Have a great day.