1. Recent FDA Regulatory and Standards Updates”
The real voyage of discovery lies not in seeking
new landscapes but in seeing with new eyes
Marcel Proust “
Recent FDA Regulatory and Standards Updates

2. Logistics Use the Zoom Chat window at any time
Direct questions at any time using the chat window. The moderator will decide if a question needs to be discussed at that point of time or towards the end.
Deck & Recording will be made available to participants

3. Agenda - Recent FDA updates that affect nonclinical SEND submission
About PointCross
Recent Regulatory Updates
Updates to Study data Validation Rules
New version of Business rules has been published-v1.4 ( We noticed website change on October 11th , 2018)
FDA published new version of validation rules - v1.3 (( We noticed website change on November 8th, 2018)
FDA technical conformance guide new version is released – v4.2 (October 30th, 2018)
Ongoing Standards Updates
CDISC SEND conformance rules draft version are under review
CDISC SEND DART conformance rules draft version are under review

4. About PointCross

5. About PointCross Life Sciences
PointCross Life Sciences is a wholly owned subsidiary of PointCross Inc.
Founded Nov 1999; focus on BioPharma since 2009
Technology for BioPharma - Big data analytics, search analytics, warehousing of structured and unstructured data from natural processes
SEND related Services for preparation and Quality checking of SEND data
Freely distributed MySEND tools with Validator to check CDISC, FDA and other Rules.
CDISC Platinum member and contributed to SEND since 2003
Global Clients in Big Pharma and Bio Tech
Leading provider of SEND standardization and quality assurance
services
FDA contractor and provider of technology
Locations – Foster City, CA; Silver Spring, MD; Paris, France; Bangalore, India
Gartner “Cool Vendor” in Life Sciences in 2013

6. Xbiom© Suite for Research & Regulatory in Clinical & Nonclinical
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Insights: Nonclinical
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MySEND – Free Downloadable Desktop tool
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Regulatory: Clinical
Regulatory: Nonclinical
Data
Standardization
SEND-ASSURE Services

7. New version of Business rules and Validator rules

8. Study Data Validation
FDA Study data Technical conformance guide (
Requires all submitted data to conform to validation rules (
Discrepancies must be explained in the nSDRG (

9. FDA Business Rules - tumor.xpt
Update
Issue
Our Current Approach
Additional 14 rules to check consistency between mi.xpt and tumor.xpt.
There is no corresponding FDA validator rule yet
PointCross (PC) rule IDs has been allotted to our Validator rule sets with which to check this.
Recommendations – If you are doing a Carcinogenicity study with us, we will do this check manually for now.

10. FDA Business Rules : Submission related
Business Rule ID
Business Rule Description
Our Current Approach
FDAB069
Drugs and metabolite names in pharmacokinetic datasets should be consistent with naming in other datasets across a submission
Through SEND ASSURE we can Provide a manual check across studies
FDAB070
Standardized units should be consistent for a given drug or metabolite across pharmacokinetic datasets within a submission
FDAB071
A specimen material type should be named consistently across pharmacokinetic datasets within a submission
This implies checking and possible corrective action across studies in a submission – e.g. Re-standardize SEND to a common CT version for multiple studies within a submission

11. FDA Validator Rules v1.3
FDA Validator Rules v1.3 :
Update
Issue
Our Current Approach
Addition of 111 CDISC conformance rules for SEND
@ CDISC - Data conformance rules for SEND are still pending GGG sign-off
These rules are already in our road map and will be available as part of our MySEND Alpha Version by Jan, 2019
Addition of Validator Rule IDs
None
Not all FDA Business rules have corresponding validator rules
Anticipatory Building and Tracking of validation rules
PointCross validator rules and IDs are issued as place holders until FDA releases their rules
Addition of SEND 3.1 applicability. There are 10 new rules applicable only to SEND 3.1
These rules will be added to the PC validator
Addition of FDA validator message
Addition of Publisher name (FDA, CDISC) and Published ID

12. Study Data Technical Conformance Guide - v4.2
SEND Updates
Study Data Technical Conformance Guide - v4.2

13. SEND Domains Domain Update Our Current Approach ts.xpt for tumor.xpt
Sponsors submitting a tumor.xpt file or non-SEND data should also provide a simplified ts.xpt.
PointCross MySEND tool generates simplified TS.xpt file that is valid for legacy studies and tumor.xpt. TS
Appendix C section added with 41 parameters, using CDISC controlled terminology for a list of parameters that should be included in the Trial Summary (TS) dataset where relevant for nonclinical studies.
PointCross currently uses CDSIC CT for TS parameters
STUDYID
TSPARMCD
TSVAL
‘study ID in the study tagging file’
STSTDTC
yyyy-mm-dd

14. SEND Domains Domain Update Our Current Approach BG
It is not necessary to include a BG domain in CDER submissions
PointCross currently generates BG on customer request.
We will add a Spot Check feature to MySEND so that QA can quickly check If a reported (PDF) BG value matches that which is calculated from SEND
LB, VS, EG
Baseline flags are expected for parallel design studies
PointCross uses Baseline flags if present in source data CO
Comments submitted in the CO domain should be relevant to study interpretation.
PointCross uses comments as present in source data

15. SEND Domains - LB Domain Update Our Current Approach LB
Results reported as incidence counts rather than summary statistics (i.e. mean and standard deviation) should be placed in LBSTRESC even if the categories are numbers & LBSTRESN should be null. This is particularly applicable for urinalysis tests where the results are values on a scale.
PointCross currently does this where appropriate
When a laboratory test result is either above or below the limit of quantification (LOQ) for the measurement method and this result was used in calculation of group means in the study report, the value used for calculation should be submitted using the supplemental qualifier variable --CALCN.
PointCross will use CALCN where appropriate in current and future studies

16. SEND Domains - PC Domain Update Our Current Approach PC
When a test result is below a LOQ:
PCORRES should contain the actual/verbatim test result.
The value of ‘BLQ’ should be in PCSTRESC to signify that the result is below the LOQ.
PCSTRESN should be blank.
Standardized units for LOQ should be in PCSTRESU.
PCLLOQ should be populated.
When a numeric value has been assigned to a result that is below the LOQ for the purpose of group summary statistics, that value should be submitted in SUPPPC as QNAM= ‘PCCALCN’ to allow the group statistics presented in the study report to be reproduced. When a value that is below the lower LOQ is excluded from group statistics, no PCCALCN entry is needed.
We have been following these guidelines with respect to PC domain.
For SUPPPC, we have made the changes as per updated guideline

17. Define.xml Update Issue Our Current Approach
For nonclinical studies, the define.xml StudyName element value must contain the sponsor’s study identifier, consistent with the study identifier used in the eCTD folder structure under Module 4
In cases where studies are out sourced to a CRO, Sponsor study identifiers are often found missing.
We will request CROs to provide the Sponsor Study Ids which will be used to populate the StudyName element.
For studies outsourced to a contract test facility, the alternate study identifier assigned to the study by the testing facility, which is typically included in the STUDYID field of the SEND datasets, should be included in the ProtocolName element value in define.xml.
None

18. Other important Guidelines for SEND

19. SEND Domains - MI Domain Update Our Current Approach MI
Non-neoplastic findings in STRESC should be standardized and limited to only the base pathological process to ensure that data can be
tabulated. For suggestions as to what constitutes a base pathological process, refer to the CDISC NONNEO CT list.
PointCross currently does this where appropriate
Result qualifiers for which there are variables available (e.g. MISEV, MIDTHREL, MICHRON) should be placed appropriately and not duplicated in MISTRESC or SUPPMI
When using a CDISC CT version before 2018 and MI severity data are collected on a scale that cannot be represented using the CDISC MISEV codelist without a loss of scientific accuracy (e.g. data were collected on 3 levels or 4 levels but MISEV specifies 5 levels), severity scores may be represented in MISEV as “1 OF 4” “2 OF 4” or “1 OF 3” as appropriate.

20. SEND Domains - SUPP Domain Update Our Current Approach SUPP
A SUPPQUAL dataset is a special SEND dataset that contains non-standard variables which cannot be represented in the existing SEND domains.
Discussion with the review division should occur if the sponsor intends to include important variables (i.e., that
support key analyses) in SUPPQUAL datasets and this should be reflected in the nSDRG.
We have been following these guidelines with respect to SUPP domain.

21. SEND Timing Variables – VISITDY, NOMDY
Domain
Update
Our Current Approach
Findings Domains
Use VISITDY or --NOMDY variable appropriate to the selected SENDIG version if findings, which were intended to be analyzed together, were collected across multiple study days.
For MA, MI, and OM, indicate groupings of grace day data collections using VISITDY or DSNOMDY variable in DS.
For in-life findings domains like LB or EG, add VISITDY or --NOMDY to the domain to indicate grouping of measurements across grace days when measurements are grouped in the Study Report.
If findings are grouped for analysis in the Study Report, VISITDY or --NOMDY should be provided for all collections to provide traceability in the SEND dataset.
We have been following these guidelines for findings domains.

22. eCTD specifications
eCTD specifications

23. M4 – Datasets folder structure
For rodent carcinogenicity studies submitted in , the tumor.xpt file and its associated define.pdf should be placed in analysis/dataset/legacy.

24. Other updates

25. Special Characters: Variables and Datasets
Variable names, as well as variable and dataset labels should include American Standard Code for Information Interchange (ASCII) text codes only.
Variable values are the most broadly compatible with software and operating systems when they are restricted to ASCII text codes (printable values below 128).
Use UTF-8 for extending character sets; however, the use of extended mappings is not recommended. Transcoding errors, variable length errors, and lack of software support for multi byte UTF-8 encodings can result in incorrect character display and variable value truncations.
Ensure that LBSTRESC and controlled terminology extensions in LBTEST do not contain byte values as some character mappings in that range may interfere with agency processes.

26. New Appendices added – SEND
Appendix C: Trial Summary (TS) Parameters for Submission – Nonclinical
41 parameters, using CDISC controlled terminology
Appendix D: Additional Documents Evaluated By FDA
Confirmed Data Endpoints for Exchange (CoDEx) for SENDIG v3.0 Data
Appendix E: Example Study Data Folder Structure
Appendix G: Example Of Simplified TS Dataset For Nonclinical Data

27. Ongoing Standards Updates

28. CDISC Conformance Rules - SEND
CDISC SEND conformance rules draft version
256 data conformance rules for SEND IG 3.0
These rules helps to evaluate study data conformance against SEND IG 3.0
Current Status: Under Working group Internal review
CDISC SEND DART conformance rules draft version
Rules are under development
Dependent on rules for SEND 3.1
2020 targeted completion (Source: SEND F2F Fall-2018)
Scope: For SEND DART IG 1.1
Embryo-Fetal Developmental Toxicity Studies

29. Q&A

30. PointCross Life Sciences
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