How to Submit Non-Clinical Data to CBER Using SEND : Understanding New FDA Requirements.pptx

What You Will Learn

The FDA’s CBER will begin requiring electronic submissions of nonclinical data to be submitted using the 3.1 and 3.1.1 versions of CDISC SENDIG on March 15th, 2023. With these requirements taking effect soon, Sponsors need to understand how to meet the new rules and regulations provided by SEND, as failing to meet them could result in FDA refusal.

In this webinar, a cross-functional team of statistical programmers and regulatory experts will share actionable insights to help study teams prepare for the new requirements.

Attendees will learn how to:
Understand nonclinical study data submissions to CDER and CBER
Differentiate biologics from drug submission in non-clinical studies
Prepare for this change to ensure a successful submission.
Solve the challenges of a SEND package
Ensure compliance with both SEND 3.1 and 3.1.1 for submission of nonclinical data to CDER and CBERHo
Separate SEND IG DART 1.1 from SEND IG
Manage legacy studies and studies that already meet requirements
Differentiate between submission packages
Use the FDA’s data standard catalog, technical conformance guide and controlled terminology

Who Will Benefit from Attending?

Regulatory Affairs and Submissions Professionals
Pharmaceutical Data and Programming Professionals
Nonclinical/Preclinical Development Professionals

1. How to Submit Non-Clinical Data Using SEND to CBER: Understanding New FDA Requirements

2. Our Presenters Satyapal Ingle, MS Senior Manager, Statistical Programming Venu Kumar Kasula Sr. Statistical Programmer , Statistical Programming Jami Gentry  Technical Manager, Regulatory Operations P Hima Bindu Sr. Statistical Programmer ,  Statistical Programming

3. 3 Poll What job roles are in the audience today?  Data Management Programming Biostatistics Medical Writing Pharmacovigilance and Medical Writing

4. 4 FDA’s CDER and CBER CDER: Center for Drug Evaluation and Research, is part of FDA and regulates the prescription and OTC drugs, including biological therapeutics and generic drugs. It also makes sure the safety and effectiveness of these drugs. CBER: Center for Biologics Evaluation and Research is one of the center within FDA, and its mission is to protect and enhance the public health through the regulation of biological and related products. It makes sure these products are safe and effective and are available to those who need them.

5. 5 FDA’s CDER and CBER Source materials (excluding vaccines or allergens) Products from non-human animal or solid human tissue sources (excludes animal derived – vaccines, RBC etc.) Antibiotics as defined by section 507 (a) of FD&C act. Some agreed upon classes of substances produced by bacteria or fungi e.g., disaccharidase inhibitors, HM Chemically synthesized molecules (excluding vaccines and allergenics) including – products produced by chemical synthesis that are intended to be analogies of cytokines, thrombolytics, mono or aturally occurring substances from minerals and plant polynucleotide products, products complementary to RNA or DNA etc. Hormone products regardless of method of manufacturing e.g., insulin, HGH, pituitary hormones. CDER: Drugs and antibiotic Products (Chemically synthesized) Vaccines regardless of method of manufacture including those at effective date of agreement being studied under active INDs administered by CDER In vivo diagnostic allergenic products or tests for DTH and allergens Human blood or human blood derived products Immunoglobulin products, whether monoclonal or polyclonal, produced in humans, animals or in cell culture. Products containing intact cells or microorganisms including bacteria, fungi, viruses etc. Protein, peptide or carbohydrate products produced by cell culture except from antibiotics, hormones. Protein products produced in animal body fluids by genetic alteration of the animal Animal venoms or constituents of venoms. Synthetically produced allergenic products that are intended to specifically alter the immune response toa specific antigen or allergen. CBER: Biological and related products (from Living source)

6. 6 Exception And Combination Products  All products that are subject to approved or pending NDAs or BLAs will remain to the center it is currently administers the NDA or PLA New products that use the same active ingredients will be settled by the CBERCDER jurisdiction committee Combination products where one or more drug and one or more biologics will be assigned based on the product's primary mode of action Categories of therapeutic biological products transferred to CDER-  Monoclonal antibodies for in vivo use. Proteins intended for the therapeutic use, including cytokines (e.g., interferons), enzymes (e.g., thrombolytics and other novel proteins, except those that are specifically assigned to CBER.  Immunomodulators (non-vaccine and non-allergenic products) 

7. 7 Nonclinical Studies PD, PK, Toxicology – SD, RD, Genotoxicity, Carcinogenicity, DART, Source: Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies

8. 8 Poll How many review offices does CBER have? 2 3 4

9. 9 Nonclinical Studies Estimation of first dose in humans: all the nonclinical studies needs to be considered but NOAEL GIVES most important information. Exploratory clinical studies in humans: the dose can be estimated on less or different nonclinical data. Primary: - Determine how intervention causes body to react -in vivo or in vitro Secondary: -determine how intervention acts on other aspects of body Safety: – identify undesirable effects on important physiological functions Pharmacodynamic (PD) ADME: Absorption Distribution Metabolism Excretion Toxicokinetic Pharmacokinetics (PK) Single Dose: determine toxicity profile Repeat Dose: determine toxicity profile Genotoxicity: detect potential interaction with DNA or chromosomes Carcinogenicity: 2-year DART: fertility, teratology, peri and post natal Toxicology

10. 10 Poll As per FDA, study initiation date means the date the protocol is signed by the study director. True False

11. The FDA support and requirements for CDISC SEND requirement (dates to conform to SEND)  SEND IG versions   11 CDER: Requirements And Support Started Source: FDA Requirements for Providing Datasets for Nonclinical Studies in SEND Format. Certara

12. 12 CBER Requirement: SEND version 3.1 and3.1.1 for CBER (FDA Data Standard Catalog The SEND IG guide the industry about the structure, organization and format of standard nonclinical tabulation datasets for exchange between organizations (CROS and sponsors) and for submission to the FDA. NDA, BLA, ANDA and Commercial IND qualifying studies initiated after– March 15, 2023. (CBER requirement date).

13. 13 Prepare for this Change to Ensure a Successful Submission Build a SEND team with SME’s Team with knowledge in different types of Non-clinical studies         and expertise in respective IG’s (SEND v3.1.1, SENDIG-DART v1.1, SENDIG-AR v1.0 ) Have standard documents in place:  Specification Template (which is metadata driven and can be updated accordingly as per version upgrade) Related WP's and SOP’s Familiarity and adherence with FDA’s data standard catalog, Technical conformance guide and utilize related controlled terminology and  codetable mapping files Have Internal quality check lists for validation along with p21

14. 14 Solve the Challenges of a SEND Package Identify the initial requirement for submission to create simplified TS.xpt Train the team on SEND guidelines Follow standardization process throughout the steps with transparency and precision by understanding the requirements and ensuring the quality Communication with the organizations is important for merging data from several sources Automation of these activities where possible is important to bring in efficiency Up versioning of the studies, to make them submission ready Staying ahead of anticipated changes and get prepared with the new changes and upgrade accordingly with the up versioning of IG’s

15. 15 Poll Have you ever provided support for a SEND submission? Yes No

16. 16 CDISC Standards for SEND SENDIG v3.0. v3.1, v3.1.1,  SENDIG-DART v1.1, SENDIG-AR v1.0 are developed The SENDIG is designed to support data typically found in single-dose general toxicology, repeat-dose general toxicology, and carcinogenicity studies, as well as respiratory and cardiovascular testing conducted during safety pharmacology studies Additional SENDIGs have been developed to support other study types. For example, SENDIG-DART v1.1 supports submission of data from nonclinical Developmental and Reproductive Toxicology (DART) studies and SENDIG-AR v1.0 supports the submission of data from studies conducted under the Animal Rule

17. 17 The SENDIG Standard Domain Models Source: SEND IG

18. 18 Significant Changes Included In v3.1   The variable VISITDY has been reclassified from Expected to Permissible, and three new variables were added to relevant domains (--USCHFL, --NOMLBL, --NOMDY). VISITDY will be phased out of the SENDIG over the time Two new domains for Safety Pharmacology studies have been added: Cardiovascular (CV) and Respiratory (RE); Vital Signs domain has been updated FOCID is available to all general observation classes to specify a study-specific point of interest Microscopic Findings domain updated, added three new variables (FOCID,--CHRON, --DISTR) Updated ECG Test Results domain, added two new Timing variables (--STINT and   --ENINT)

19. 19 Significant Changes Included In v3.1.1 SENDIG v3.1.1 introduces revisions to the Pharmacokinetic Concentrations (PC) Domain and the Pharmacokinetic Parameters (PP) Domains focused on providing instruction and examples to improve standardization of these data Changes to the expectancy or "Core" value for some timing variables were made for more consistent use by data consumers which can be used in creation of Time/Concentration Curves. PCBLFL, PCDTC changed to Perm, PCELTM, PCTEPREF changed to Exp. New variable PCUSCHFL included. New examples are provided to show the relationship between concentration data and their relevant parameters Cross-domain examples now show how the domains EX, PC, PP, SUPPPC and POOLDEF work together for a study Examples include how best to represent an unscheduled concentration sample, as well as different ways of qualifying AUC tests

20. 20 Domains Introduced in Developmental And Reproductive Toxicology (DART) IG

21. 21 Domains Introduced in Animal Rule (AR) IG

22. 22 An Overview of Differences Between SDTM and SEND SEND has trail design domains like TA, TE, TX (Trial Sets) and TS but no TV domain TX domain provides the list of distinct sets of subjects having different experimental factors, treatment factors, inherent characteristics, or distinct sponsor designations as specified in the trial design

23. 23 Details of Domains in SEND In SEND domains like Body Weight (BW), Body Weight Gain (BG), Clinical Observations (CL), Food and Water Consumption (FW), Macroscopic Findings (MA), Organ Measurements (OM), Palpable Masses (PM) are present in general observation class in addition to other domains. Body Weight (BW) BWBLFL, BWFAST, BWREASEX Body Weight Gain (BG Difference of weights

24. 24 Details of Domains in SEND Clinical Observations (CL) CLRESCAT Food and Water Consumption (FW) POOLID. POOLDEF dataset can be created for relating/grouping the records. Organ Measurements (OM) Organ weights and ratio of Organ to body weight. Palpable Masses (PM)  Test parameter selection depends on the actual data collection.

25. 25 Details of Domains in SEND In SEND  assessments like TEMP to be captured in VS domain. SYSBP, DIABP etc. are captured in CV domain and Respiratory (RESP) information is captured in RE domain. SDTM: VS domain includes Blood Pressure, Respiratory  and Temperature measurements SEND: VS domain captures only TEMP, Blood Pressure related measurements in CV domain and Respiratory related  measurements in RE domain

26. 26 Variables introduced in SEND As VISITDY is associated with the clinical encounter (VISIT), it is not the appropriate variable to represent hence, VISITDY has been phased out of the SENDIG and initially replaced with reporting variables (--NOMDY and --NOMLBL)  --NOMDY is used to group records collected over multiple days under a single nominal study day for reporting purposes --NOMLBL is a label for a given value of --NOMDY as presented in the study report (e.g., "Week 4", "Day 28", "Terminal Sac")

27. 27 SDTM Variables to Never Use in SEND

28. 28 What submission types require electronic data submission? Certain investigational new drug applications (INDs) New drug applications (NDAs) Abbreviated new drug applications (ANDAs) Certain biologics license applications (BLAs) What submission types are exempt from electronic data submission? All submissions regarding noncommercial INDs (including investigator-sponsored INDs and expanded access INDs, e.g., emergency use and treatment INDs)

29. 29 Tabulation Dataset (Nonclinical) Define.xml Reviewer’s Guide.pdf (nsdrg.pdf) datasets in . xpt For CDER, Simplified ts.xpt is sufficient for studies which start date is prior to Dec. 17, 2016 (for NDAs, BLAs, ANDAs) or Dec. 17, 2017 (for commercial INDs) and similarly for CBER any studies with start date prior Mar. 15, 2023 (for NDAs, BLAs, ANDA and commercial INDs.) SEND data packages must always include a  ts.xpt  file, simplified or full. *No  aCRF  and no Program files in SEND SEND Dataset Package At a minimum, a simplified ts.xpt , (whether study contains xpt datasets other than ts.xpt )  Client should confirm with the agency when submitting Legacy packages. In some cases, clients convert legacy data to CDISC standards, and the agency requests they submit the Legacy AND the CDISC compliant data for each study for “traceability”. In these cases, additional data may be required (e.g., aCRF , legacy tabulation data, etc.) Older data that does not comply with CDISC standards. Legacy Dataset Package

30. 30 Tabulation Dataset - SEND Simplified ts.xpt A "simplified" ts.xpt must be submitted any time there is a study report included in eCTD Modules/Sections 4.2.3.1, 4.2.3.2, or 4.2.3.4. Otherwise, the validation will give a high error code 1734. If it is not, the date will prompt the validation tool to look for the Demographic (DM) dataset and define.XML (error code 1736). For studies with a start date that  does not  exempt from submitting SEND datasets, it is vital that the TSVAL domain is blank. 

31. 31 Tabulation Dataset - SEND Simplified ts.xpt If the study start date exempts from submitting SEND, use this format: If the study start date does not exempt from submitting SEND, the TSVAL domain has to be blank (as shown below) or additional validation errors will appear

32. 32 Electronic Submission Organization

33. 33 Reg Ops Considerations For submissions to CDER, SEND datasets are required when submitting a draft report as these data form the basis of regulatory decisions regarding nonclinical support for clinical development. SEND datasets will not be required for CBER submissions until after March 15, 2023 . If there are changes to the SEND datasets requiring resubmission with the final study report, updated datasets should be resubmitted using the ‘ replace ’ operator.   SEND datasets would not need to be resubmitted with the final report if there were no changes to the dataset from the draft report. Even when SEND datasets do not need to be resubmitted, it is recommended that an updated nSDRG is submitted with the final study report. This updated nSDRG should include the current study report version (Section 1.1), any date (or administrative) changes, and a notation that no changes to SEND datasets were made or needed other than the notation of the version change (e.g., STRPSTAT change) after the draft report is submitted.

34. 34 Reg Ops Considerations T he value for [study-id] used in the STF should be included in TS using the parameter SPREFID. Though SPREFID is not in the SDTM controlled terminology for TSPARMCD, SPREFID should be used to reconcile study identifiers where necessary for SEND or SDTM studies . FDA will use SPREFID to match study identifiers across STF and TS to establish the study start date where necessary for evaluation against the eCTD validation criteria.

35. 35 Any last considerations from our panel?

36. 36 Any questions? Satyapal Ingle, MS Senior Manager, Statistical Programming Venu Kumar Kasula Sr. Statistical Programmer , Statistical Programming Jami Gentry  Technical Manager, Regulatory Operations P Hima Bindu Sr. Statistical Programmer ,  Statistical Programming

37. 37 Guidance Documents And References FDA Data standard catalog Study Data Technical rejection criteria Study Data Technical conformance guide SEND | CDISC Index of /ftp1/CDISC/SEND (nih.gov) https://www.cdisc.org/system/files/members/standard/terminology/SEND_Codetable_Mapping.xlsx