1. DIA Electronic Submissions Meeting Olga Alfieri 26 April 2016
Highlights of US FDA Regulatory Compliance Roadmap and SEND Standardized Study Data Requirements
DIA Electronic Submissions Meeting Olga Alfieri 26 April 2016

2. Outline Highlights of FDA Submissions Compliance Roadmap What is SEND?
SEND Implementation Timing
SEND Strategies Timetable (Example)
Studies in Scope for SEND under SENDIG V3.0
How to Prepare for SEND READINESS –Experience
Submitting a Pilot to FDA (Back-up Slides)
Backup Slides

3. Highlights of FDA Submissions Compliance Roadmap
2016
2017
2018
2019
NDA, ANDA, BLA and Master files must be submitted in eCTD format beginning in May 5, 2017*
05May17 (Ver 3.2.2)
Commercial IND submissions must be submitted in eCTD beginning May 5, 2018
05May18
SEND Datasets**
Studies starting after Must Use the Standards in the Data Catalog
17Dec
Ad/Promo (OPDP-2253)***
2017 (Ver 3.3)
*eCTD is still not mandatory
** New Studies written after Dec 2016 ***Ad/Promo accepts submissions via ESG since 15Jun2015 – New M1 was released 15Jun2015

4. FDA Draft Guidance on Electronic Submission Standards
The FDA published the FINAL Binding Guidance
What Submission Types are Applicable
Source: FDA Website

5. FDA Published Binding Guidance on 12/17/2014

6. Data Standards Catalog (DSC) The version of eCTD currently supported is specified in the DSC
DSC lists formats for study data that FDA can process, review, and archive
Includes required and/or supported versions
Key dates for each standard – Requirements and Support begins/ends
No waivers for eStudy requirements, though possible for data standard versions in DSC

7. What eCTD Formats will be Required?
You need to refer to the Data Standards Catalog to ensure you are submitting the latest version of Data Standards
Recommendation: Ref to FDA DSC for upcoming IND/NDA submission planning

8. What is SEND? Standard for Exchange of Nonclinical Data
The nonclinical electronic standard is referred to as SEND (Standard for the Electronic Submission of Nonclinical Data)
In development over 12 years by CDISC in collaboration with FDA
SEND is the same electronic standard used by Clinical for FDA Submissions

9. What is SEND (cont’d)? Standard for Exchange of Nonclinical Data
The CDISC SEND model is an implementation of the Study Data Tabulation Model (SDTM) for the submission of nonclinical studies
SEND will facilitate the submission of standardized nonclinical safety pharmacology and toxicology study data in INDs and NDAs
Developed by the CDISC SEND team for formatting of data collected from nonclinical safety pharmacology and toxicology studies

10. SEND MANDATORY TIMETABLE
Submission Type
Timing
NDA, ANDA, and certain BLA submissions
Studies which start after (December 18th, 2016)
Commercial INDs and amendments, except for submissions described in section 561 of the Federal Food, Drug, and Cosmetic Act
Studies which start after (December 18th, 2017)
Source: Phuse Website

11. Examples – SEND Strategies
Type
Study Initiation Date on Or After
SEND Strategies – Best Practices
NDA
Submitted before 18 Dec 2016
NDA submitted to CDER before 18 Dec does not need to be submitted in SEND format (although it is preferred
Submitted after 18 Dec 2016
NDA submitted to CDER after 18 Dec needs any studies which started after 18 Dec 2016 to be submitted in SEND. The other studies in the submission do not need to be submitted in SEND format (although it is preferred)
IND
Submitted before 18 Dec 2017
IND submitted to CDER before 18 Dec does not need to be submitted in SEND format (although it is preferred)
Submitted after 18 Dec 2017
IND submitted to CDER after 18 Dec needs any studies which started after Dec 2017 to be submitted in SEND. The other studies in the submission do not need to be submitted in SEND format (although it is preferred)
Source: Phuse Website

12. What Studies are in Scope for the Current SENDIG Version 3.0?
In-Scope Now:
Single-dose general toxicology
Repeat-dose general toxicology
Carcinogenicity studies
Future Versions are in development:
Safety Pharmacology
Reproductive Toxicology
Timelines Unclear when FDA will accept

13. Benefits of SEND To CDER
Aligned with CDER’s goal of rapid acquisition, analysis, storage and reporting of regulatory data
Improve efficiency
Improve regulatory science
Pharmacologists and toxicologists can determine the nonclinical parameters that best predict adverse events in humans
Improve quality of reviews
Improve information in written review to demonstrate basis for decisions
Supports FDA’s efforts to develop a repository for all submitted study data (Janus)

14. Benefits of SEND
SEND defines how to format nonclinical data once it is captured
Accommodates the sponsor’s study design, conduct, and data capture methods
Provides a standardized, electronic presentation of toxicology study data tabulations
Enables the development and use of visualization and analytical tools for these types of data
Enables more effective and efficient review of nonclinical toxicology data
Will replace data tabulations in study reports

15. What SEND Does Not Do?
SEND does not change data or impose new study requirements
SEND will not replace summary, interpretive or other information in study reports.

16. SEND Pilots Programs at FDA SEND Dataset Pilot Review
FDA is encouraging the industry to submit sample SEND datasets for technical review Note: Process for submitting sample datasets is available on the FDA Website and provided in the backup slides in this presentation.
FDA is accepting pilot SEND Submissions in which Sponsors submit SEND files
FDA will process the SEND submission pilot for compliance based on the current standard model and SEND processing rules.
Note: The SEND pilot process should be considered as best practice for all companies submitting SEND datasets. Lack of compliance can result in a submission delay.

17. Benefits of Submitting a SEND Pilot for Review
FDA will provide
Valuable information regarding your dataset’s compatibility with the FD systems
Confirm if your sample dataset was able to successfully load into NIMS database
Provide results to view any errors/warnings produced in your sample SEND dataset
Provides you the opportunity to you address any technical issues before you submit a major submission and to discuss with FDA regarding technical requirements

18. Submit Sample Submissions to FDA
Request a Sample Application Number
To initiate the process of submitting a SEND sample, the Electronic Submission Support Team at to inform them of our intention of submit a sample with following information:
Contact Person Name (this will be the main contact during the sample submission phase)
Contact Person's Company Name
Contact Person's Mailing Address
Contact Person's Phone Number
Contact Person's Address
Date When You Plan To Submit An Actual Application
Description of Sample to be evaluated including application type if known (e.g., eCTD/IND, ANDA, NDA, or DMF; eCTD Cross Application Linking; CDISC/SDTM, CDISC/ADaM or CDISC/SEND dataset)
Note:
The FDA is encouraging the industry to submit sample SEND datasets for technical review and the FDA described the process for submitting sample datasets. It is important to closely follow the process described on the FDA website to avoid potential delays in the review process.

19. Sample Email for Request a Sample Application Number
Note:
The FDA is encouraging the industry to submit sample SEND datasets for technical review and the FDA described the process for submitting sample datasets. It is important to closely follow the process described on the FDA website to avoid potential delays in the review process.

20. Process for Submitting a Sample SEND Submission to FDA
Technical representative from the FDA will contact you and assign a number for the sample, along with additional instructions. (This may take about 2~4 business days or more)
Note:
The FDA is encouraging the industry to submit sample SEND datasets for technical review and the FDA described the process for submitting sample datasets. It is important to closely follow the process described on the FDA website to avoid potential delays in the review process.

21. Process for Submitting a Sample SEND Submission (Cont)
Submit Sample Submission using the Specifications
Electronic Submission Support Team will Process the Sample Submission
to ensure that it conforms to FDA guidance and specifications as well as ICH specifications and guidelines
test against eCTD validation
Electronic Submission Support Team provides a report highlighting the errors found during the initial processing of the sample submission
The CDISC/SDTM, CDISC/ADaM or CDISC/SEND validation for sample submissions will produce an error report created by OpenCDISC, along with any additional observations by the Team
Resolve any Technical Issues with the Submission
Resubmit the Sample Submission

22. How to Prepare for SEND READINESS (Experience)
Recommend you create an internal SEND Workstream to map the SEND Readiness
Create an Implementation Timing Table
Controlled Terminology Mapping
Define Data Validation Process (Critical Steps)
Develop Checklist Process for Vendor/Internal Stakeholders
Create Study Data Reviewer’s Guide Template for SDTM/ADAM
Develop SEND SOP/SWP/QA/QC Checklist
Develop Internal Work Procedure Documents
Naming conventions
How to handle legacy data
How to split Datasets and provide a naming convention
Submit a Pilot
Discuss Regulatory Strategies from IND to NDA submissions
Data Version from IND to NDA Submission (Tracking)

23. Example of SWP TOC

24. Study Data Reviewer’s Guide
A Study Data Reviewer’s Guide (SDRG) is considered by FDA to be an integral part of every SEND submission
The primary purpose of the SDRG is to explain any differences between the SEND datasets and written report.

25. Final Comment
FDA (CDER) is ready now and help is available to sponsors wishing to submit their nonclinical data electronically
Questions regarding submissions of electronic, standardized data can be sent to
Test submissions for validation

26. Thank you!

27. Backup slides

28. Clinical Data Interchange Standards Consortium (CDISC)
CDISC is a global, open, multidisciplinary, non-profit organization that has established standards to support the acquisition, exchange, submission and archive of clinical research data and metadata. The CDISC mission is to develop and support global, platform-independent data standards that enable information system interoperability to improve medical research and related areas of healthcare. CDISC standards are vendor-neutral, platform-independent and freely available via the CDISC website

29. Note to Sponsor
The information provided in request for a sample number should also be provided in the cover letter of sample submission
Testing phase does not involve any review of the content of the submission and is intended to only resolve technical issues

30. Data Validation (Critical Steps)
Validation of a SEND dataset against the standard SEND model is a critical part of the SEND process.
OpenCDISC validator to validate SEND datasets against the SEND (version 3.0, latest release) standard model. OpenCDISC validator is also used by the FDA.
The OpenCDISC validator produces a validation report that will identify any areas in the SEND dataset that are not in compliance with the SEND standard and will classify them according to validation errors, warnings, and notices. Validation errors but not warnings or notices will prevent a SEND dataset from being loaded into FDA’s review software.

31. To Learn about SENDIG V3.0 Link to production version of SENDIG
Downloads
References
SEND Educational Opportunities