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
The 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_C
odetable_Mapping.xlsx

38. Thank you!
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