The document discusses standards for clinical trial data submission, including: - Regulatory agencies are pushing for standardized data submission to improve review efficiency under PDUFA. CDISC standards including SDTM and ADaM are becoming required. - CDISC regularly updates and expands clinical data standards to include new domains and enhancements. - A properly constructed define.xml file documenting the metadata is important for reviewers to understand the data.

1. Geneva Branch
THE DO’S AND DON’TS OF DATA
SUBMISSION
- Biometristi Italiani Associati – V Annual Congress
Università Bicocca – Milano - 24-25/10/2013
Angelo Tinazzi
Cytel Inc., Wilmington Del. USA
Succursale de Meyrin – Geneva – Switzerland
angelo.tinazzi@cytel.com

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THE DO’S AND DON’TS OF DATA SUBMISSION
Disclaimer
The information contained in this
presentation is based on personal
research of the author and does not
necessarily represent Cytel Inc..
Geneva Branch

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THE DO’S AND DON’TS OF DATA SUBMISSION
A Failied Submission
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
A Failied Submission
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
 Missing Variables and Mislabeled Variables
 Datasets are presented in a way that remains
confusing despite diligent and repeated efforts to understand
the presentation
 The problems these issues cause prevent even an initial
cursory verification of the primary and
secondary endpoints of the XXXXX trial let alone
any more sophisticated analysis
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
A Failied Submission
Datasets Deficiency
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
A Failied Submission
Geneva Branch
A Failed Submission
Datasets Deficiency
Agencies
A world of Standards
Variable
Name
Variable
Label
Type Decode
/Format
Origin
OCS1DT
Date of first
recurrence
Num
Derived See derved datasets
specs page 125
Date9
Comment
No link provided
Variable
Name
Variable
Label
Type Decode
/Format
Origin
OCS1DT
Date of first
recurrence
Num
Derived Actual date associated
with QOC1CD = 1.
FRE1SDT =
minimum FRE1SDT,
where FRE1SDT ≥ RNDT.
Date9
Comment
Variable FRE1SDT and RNDT are not in the same dataset
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
A Failied Submission
Geneva Branch
A Failed Submission
Datasets Deficiency
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
illogical Order
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
A Failied Submission
Geneva Branch
A Failed Submission
 Meet the


PDUFA V, 21st Century Review, CDER Data Standards, PhUSE/FDA and
ADaM: Getting It All Right; Steve Wilson.
PhUSE SDE - Durham, North Carolina. Thursday, April 18th, 2013
reviewer and
always be
«honest»
Clear
Communication
Create robust
Analysis Dataset
Specifications
 Claritiy
 Use plain
english
 Traceability
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Agencies pushing for Standards
Geneva Branch
A Failed Submission
Prescription Drug User Fee Act (PDUFA)
 Part of the law for Food and Drug Administration
Safety Innovation Act (FDASIA)
 Passed in 1992 allows FDA to collect fees from
Sponsors (User Fee Programme)
 In return for meeting review performance goals
 —eally works
R
 Review time decrease by half (priority) and 37%
—
(standard)
 Since 1993 over 1000 drugs were approved
 Over 50% of new drugs are launching in US
compare to 8% pre-‐PDUFA
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Agencies pushing for Standards
Geneva Branch
A Failed Submission
Prescription Drug User Fee Act (PDUFA)
 —eauthorized for 2013-‐1017
R
 —erformance Goals
P
“Review and act on 90% ….. Submissions in 10/6 months of
the 60 day filing date”
—
Improve the efficiency of human drug review
through required electronic submissions
standardization of electronic drug
application data
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Agencies pushing for Standards
Geneva Branch
A Failed Submission
Prescription Drug User Fee Act (PDUFA)
High Quality Standard of Data
CDISC data is foundational pre-‐requisite
 — akes possible the
M
 — se of standard‐based review tools
U
 Development of reusable analysis scripts
 Analysis across submissions
 — February 2012, FDA requested congress to make
In
standard data required for submissions
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Agencies pushing for Standards
Prescription Drug User Fee Act (PDUFA)
Timeline
 —ec 2012 – Draft Guidance on standards and format
D
of eSub
 +12 Months – Final Guidance released
 +36 Months – All new NDAs/BLAs to use CDISC
End 2015 / 2016 no more an option
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Agencies pushing for Standards
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Agencies pushing for Standards
What about the other Agencies?
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions
CDISC Interchange 2013

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A World of Clinical Standards - CDISC
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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A World of Clinical Standards - CDISC
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
A World of Clinical Standards - CDISC
Geneva Branch
A Failed Submission
SDTM Version 3.1.2 Dec-2011
 Amendment 1 to the SDTM V1.2 and SDTMIG
V3.1.2
 New variables in DM (e.g. DTHDTC/DTHFL and
ACTARM) and AE (e.g. additional coding variables)
SDTM Version 3.1.3
 Oncology (efficacy) domains (TU,TR,RS)
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
A World of Clinical Standards - CDISC
Geneva Branch
A Failed Submission
SDTM Version 3.1.4 (upcoming)
 SS (Survival Status)
 EX/EC Exposure Domains
 New domains: IS/SR (Immunogenicity/Skin React),
PR (Procedure), DD (Death)
 TD (Trial Disease Assessment)
 HO (Healthcare Encounters)
 AP (Associated Persons)
What’s new in draft SDTM IG 3.1.4, Nicola Tambascia,
28th June 2013, PhUSE SDE Basel
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
A World of Clinical Standards - CDISC
Geneva Branch
A Failed Submission
SDTM Version 3.1.5 (planned)
 More Oncology Domains
 More enanchements
 Lab Findings (e.g. biomarkers)
 More TA domains
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
A World of Clinical Standards - CDISC
Geneva Branch
A Failed Submission
ADaM Latest Release (2012-2013)
 ADTTE for Time-to-Event Endpoints
 ADAE for Adverse Events
 Validation Checks
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions
ADaM To come
 General Occurrences
 IG v1.1
 ADaM Integration IG 1.0
 ADaM Metatadata Guide

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THE DO’S AND DON’TS OF DATA SUBMISSION
A World of Clinical Standards - CDISC
Geneva Branch
A Failed Submission
Define.xml v2.0
Case Report Tabulation Data Definition
Specification, (CRT-DDS)
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
“A critical component of data submission is the
define file. A properly functioning define.xml file is an
important part of the submission of standardized
electronic datasets and should not be considered
optional”
“Additionally, sponsors should make certain that every
data variables code list, origin, and derivation is
clearly and easily accessible from the define file.
An insufficiently documented define file is a common
deficiency that reviewers have noted.”
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
A World of Clinical Standards - CDISC
Define.xml v2.0
 Specification for


describing data
sets (metadata)
Does not
describe how this
metadata should
be displayed;
display is not part
of the
standard
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
A World of Clinical Standards - CDISC
Geneva Branch
A Failed Submission
Validation Rules
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
A World of Clinical Standards - CDISC
Geneva Branch
A Failed Submission
Accepted Standards at FDA
Agencies





SDTM IG 3.1.3
ADaM IG 1.0
SEND 3.0
Define.xml 2.0
Validation Rules
(OpenCDISC 1.4.1)
http://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
A World of Clinical Standards - CDISC
Geneva Branch
A Failed Submission
Agencies
CDISC submission
 In 2010, CDER received an average of over 650
datasets/week, with 23% of active NDAs
containing CDISC/SDTM data
 In 2011 this number has increased to an average
39% in SDTM and 32% in ADaM
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
eCTD Rules
Geneva Branch
A Failed Submission
 The Electronic Common Technical Document (eCTD) allows for
the electronic submission of the Common Technical Document
(CTD) from applicant to regulator
 The CTD describes the organization of modules, sections and
documents.
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
eCTD Rules
Module 5: Clinical Study Reports
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
ADaM datasets,
Define.xml
ADaM SAS programs
SDTM datasets,
Define.xml, SDTM
annotated blank eCRF
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
eCTD Rules
Geneva Branch
A Failed Submission
eCTD File Format
 Protocol – pdf (i.e., study001-protocol.pdf)
 SAP – pdf (i.e., sutdy001-sap.pdf)
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
 eCRF – pdf (i.e., sutdy001-blankecrf.pdf)
What Next
 SDTM – xpt (i.e., dm.xpt, ae.xpt, ds.xpt, and etc)
Conclusions
 ADaM – xpt (i.e., adsl.xpt, adae.xpt, adtteos.xpt,
and etc)
 SEND – xpt (i.e., dm.xpt, se.xpt, bw.xpt, and etc)
 CSR – pdf (i.e., sutdy001-csr.pdf)
 Define.xml – xml or pdf (i.e., define.xml/define.pdf)
 ADaM SAS programs – txt (i.e., c-adsl-sas.txt)
 Output SAS programs – txt (i.e., t-14-01-001-ds-
sas.txt )

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THE DO’S AND DON’TS OF DATA SUBMISSION
eCTD Rules
Geneva Branch
A Failed Submission
Naming Conventions
 Lower case of letter from “a” to “z”
 Number from “0” to “9” “-” hypen
 No special character ( #, %, $ and etc)
 File name should be less than or equal to 64
characters including the appropriate file
extension
 The length of entire path of the file should
not exceed 230 characters.
(m5/datasets/study001/sdtm/ae.xpt)
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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eCTD Rules
Geneva Branch
A Failed Submission
File Guideline
 Version – 1.4 thru 1.7 are acceptable
 Fonts
 Standard : Arial, Courier New, Times Roman
 Sizes : range from 9 to 12 point ( Times New
Roman 12-point font is recommended for
narrative text )
 Page
 Print area : 8.5 inches by 11 inches
 Margin : at least ¾ inch
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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eCTD Rules
Geneva Branch
A Failed Submission
SAS XPT File Guidance
 Length
Agencies
A world of Standards
 Variable length is less than or equal to 8
eCTD Rules
 Variable label is less than or equal to 40
Meet the reviewer
 Dataset length is less than or equal to 8
 Dataset label is less than or equal to 40
 Dataset Size – less than 1 GB (LB1, LB2, and so
on)
 The length of character variables should be
minimized (i.e., if the maximum length of
USUBJID is 20 character long, keep the length as
20, not 200)
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Meet the reviewer
Geneva Branch
A Failed Submission
Pre-NDA Meeting
The objective of this meeting is to obtain guidance on
certain aspects of the Sponsor’s plans for NDA
submission. Specifically, the Sponsor seeks
agreement related to activities that must be
undertaken prior to the final submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Meet the reviewer
Pre-NDA Meeting
 Does the FDA concur with the Sponsor’s plan
regarding the composition and format of the clinical
data submission for the XXXXXXX eCTD NDA?
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions
 Do not use «Open Question», always propose
solutions and ask for confirmation

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THE DO’S AND DON’TS OF DATA SUBMISSION
Meet the reviewer
Top 7 CDER/CBER CDISC Issues
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions
More details in the backup slides
CDER/CBER’s Top 7 CDISC Standards Issues
Dhananjay Chhatre, eData Management Solutions Team, Office of Business Informatics CDER, U.S. FDA
Amy Malla, Review Management, CBER, U.S. FDA

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THE DO’S AND DON’TS OF DATA SUBMISSION
Meet the reviewer
Geneva Branch
CDER Common Data Standards Issues
A Failed Submission
 May-2011: CDER published Common Data
Agencies



Standards Issues
Dec-2011: v1.1 is published
Issued by CDER to convey
 Common Issues
 Requests for future submissions
Study Data Specifications v2.0, July 18, 2012
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Electro
nicSubmissions/ucm248635.htm
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Meet the reviewer
Geneva Branch
CDER Common Data Standards Issues
A Failed Submission
 Sponsors should refer to the latest version of
Agencies
SDTM IG
 Sponsors should refer to Amendment 1 to SDTM
V1.2
 Sponsors should ensure that every data variable’s
codelist, origin and derivation is clearly and easily
accessible in define file
 SDTM should be consistent with submitted analysis
datasets
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Meet the reviewer
Geneva Branch
CDER Common Data Standards Issues
A Failed Submission
Traceability
 Understanding relationship between the analysis
results the analysis datasets and the SDTM
domains
 Establishing the path between an element and its
immediate predecessor
 Two levels:
 Metadata traceability
Agencies


Relationship between an analysis result and analysis dataset(s)
Relationship of the analysis variable to its source dataset(s)
and variable(s)
 Data point traceability

Predecessor record(s)
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Meet the reviewer
Geneva Branch
CDER Common Data Standards Issues
A Failed Submission
Traceability
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Meet the reviewer
CDER Common Data Standards Issues
Controlled Terminology
 Use existing CDISC terminology
 If available CDISC terminology is insufficient,
sponsors should create their own terminology
 Documentation on sponsor-specific terminology
should be included in define.xml
http://www.cancer.gov/cancertopics/cancerlibrary/terminologyresources/cdisc
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Meet the reviewer
Geneva Branch
A Failed Submission
CDER Common Data Standards Issues
MedDRA and Common Dictionary
 Sponsors should exactly follow spelling and case
 MedDRA version should be consistent across
trials within the submission
 Dictionary name and version should be
documented in define.xml
More details in the backup slides
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
Meet the reviewer
Geneva Branch
A Failed Submission
PhUSE SDE; ADaM Review from a CDER Statistical
Reviewer's Perspective; Behrang (Ben) Vali. FDA
 ‘Traceability’ is the key for reviewers
 Less is NOT more
 ADaM appropriately emphasizes this
 Derived Variables SHOULD ONLY exist in
ADaM datasets
 SDTM Datasets SHOULD ONLY present the
observed data from the CRF
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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Meet the reviewer
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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What Next
Geneva Branch
A Failed Submission
More Metadata Oriented
e.g. Results Metadata
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions
Also addressed in the FDA Guidance «Semantic Interoperability»

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What Next
Geneva Branch
A Failed Submission
The FDA/PhUSE Collaboration
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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What Next
Geneva Branch
A Failed Submission
The FDA/PhUSE Collaboration
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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What Next
Geneva Branch
A Failed Submission
The FDA/PhUSE Collaboration – Optimizing the Use of Data Standards
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
What Next
Geneva Branch
A Failed Submission
The FDA/PhUSE Collaboration – Optimizing the Use of Data Standards
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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What Next
Geneva Branch
A Failed Submission
Other PhUSE Initiatives
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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THE DO’S AND DON’TS OF DATA SUBMISSION
What Next
More requirements to come
The agency uses it to facilitate use of a
risk-based approach for the timely
identification of clinical investigator sites for
on-site inspection by CDER during the
review of marketing applications
Experiences in Preparing Summary Level Clinical Site Data
within NDA’s Submission for FDA’s Inspection Planning.
Xiangchen (Bob) Cui, PharmaSUG 2013
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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What Next
Geneva Branch
A Failed Submission
Data Sharing
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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Conclusions
 Communication, clarity and honesty play a key role



in data submission
Traceability
Use of Standards
There are still Regional Differences
 (e.g. Japanese HA looks more closely at details)
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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Conclusions
 Communication, clarity and honesty play a key role



in data submission
Traceability
Use of Standards
There are still Regional Differences
 (e.g. Japanese HA looks more closely at details)
Data Submission
Geneva Branch
A Failed Submission
Agencies
A world of Standards
eCTD Rules
Meet the reviewer
What Next
Conclusions

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[A. Tinazzi]
THE DO’S AND DON’TS OF DATA SUBMISSION
Questions
New Geneva offices – November 2012
Geneva Branch

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THE DO’S AND DON’TS OF DATA SUBMISSION
More details on the following topics
• Top 7 CDER/CBER CDISC Issues
• CDER Common Data Standards Issues
Geneva Branch

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THE DO’S AND DON’TS OF DATA SUBMISSION
Top 7 CDER/CBER CDISC Issues
1. Waste of Space
 i.e. actual length = 8, allotted length = 200
 Impact on dataset size compounded by large number of
rows
 In the CDISC IG, an example references a column
length of 200. It appears this example was taken to
heart by industry
2. Extras (Domains, Variables, SUPPQUAL)
 Use common sense and discuss with review team on
whether all information in supp- datasets are necessary
(e.g. Initials)
 If “important” variables (support key analyses) are
placed in SUPPQUAL, discuss with the review team
CDER/CBER’s Top 7 CDISC Standards Issues
Dhananjay Chhatre, eData Management Solutions Team, Office of Business Informatics CDER, U.S. FDA
Amy Malla, Review Management, CBER, U.S. FDA
Geneva Branch

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THE DO’S AND DON’TS OF DATA SUBMISSION
Top 7 CDER/CBER CDISC Issues
3. Validation Errors
 Validation process results in error log -> read it!
 Errors and warnings that CAN be fixed, SHOULD
be fixed
 Some errors/warnings will inherently exist because
of your study design
 i.e. no baseline result, no exposure record
 Others won’t
 Don’t simply address and dismiss these errors in a
“Reviewer’s Guide”
CDER/CBER’s Top 7 CDISC Standards Issues
Dhananjay Chhatre, eData Management Solutions Team, Office of Business Informatics CDER, U.S. FDA
Amy Malla, Review Management, CBER, U.S. FDA
Geneva Branch

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THE DO’S AND DON’TS OF DATA SUBMISSION
Top 7 CDER/CBER CDISC Issues
3. Validation Errors – Common Errors
 Codelist mis-match for extensible codelists
 End date is prior to start date
 Required and expected variables should be present
in the dataset
 Variable labels in the dataset should match CDISC
naming conventions
 AE set to serious but no qualifier exists that has
been set to “Y”
CDER/CBER’s Top 7 CDISC Standards Issues
Dhananjay Chhatre, eData Management Solutions Team, Office of Business Informatics CDER, U.S. FDA
Amy Malla, Review Management, CBER, U.S. FDA
Geneva Branch

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THE DO’S AND DON’TS OF DATA SUBMISSION
Top 7 CDER/CBER CDISC Issues
4. Extended Codelist
 Submissions include codelists where variable
values are not included in the codelist
 Incorrect define.xml
5. ISO Dates (YYYY-MM-DDThh:mm:ss)
 Clarification needs to occur in CDISC IGs
regarding when to input times and when to
omit
 If time was captured in CRFs, include in
tabulations data
CDER/CBER’s Top 7 CDISC Standards Issues
Dhananjay Chhatre, eData Management Solutions Team, Office of Business Informatics CDER, U.S. FDA
Amy Malla, Review Management, CBER, U.S. FDA
Geneva Branch

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THE DO’S AND DON’TS OF DATA SUBMISSION
Top 7 CDER/CBER CDISC Issues
6. Traceability
 No traceability between source data and datasets
 Need linkage: CRF -> SDTM -> ADaM -> CSR
 SDTM datasets should be created from CRFs
 If instead CRFs -> Raw -> SDTM, your analysis (and



hopefully ADaM) datasets should be created from those same
SDTM datasets, not the raw datasets
Features exist in the ADaM standard that allow for traceability
of analyses to ADaM to SDTM
Creating SDTM and Analysis data from the raw data is
incorrect (especially when submitting only SDTM and
analysis data)
Raw data should create SDTM, and SDTM should then create
Analysis
CDER/CBER’s Top 7 CDISC Standards Issues
Dhananjay Chhatre, eData Management Solutions Team, Office of Business Informatics CDER, U.S. FDA
Amy Malla, Review Management, CBER, U.S. FDA
Geneva Branch

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THE DO’S AND DON’TS OF DATA SUBMISSION
Top 7 CDER/CBER CDISC Issues
7. Inadequate Documentation
 Often times not all aspects of the standard apply to
your study/submission
 Submit supporting documentation in the form of a
“Reviewer’s Guide” to explain how the data
standard was implemented:





What is in the custom domains?
What is in the suppqual’s?
Insufficient codelists?
Unfixable errors/warnings and why?
Derivation of key analysis variables
CDER/CBER’s Top 7 CDISC Standards Issues
Dhananjay Chhatre, eData Management Solutions Team, Office of Business Informatics CDER, U.S. FDA
Amy Malla, Review Management, CBER, U.S. FDA
Geneva Branch

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THE DO’S AND DON’TS OF DATA SUBMISSION
Top 7 CDER/CBER CDISC Issues
Reccomendations
 Start implementing CDISC as soon as possible
 Pre-‐NDA/BLA is too late
—
 Pre-‐IND is the best time for planning
 Communicate with FDA
 —ollow FDA guidelines and recommendations (e.g.
F
CDER Data Standards Common Issues Document)
 —ata validation errors and warning that CAN be
D
fixed, SHOULD be fixed
CDER/CBER’s Top 7 CDISC Standards Issues
Dhananjay Chhatre, eData Management Solutions Team, Office of Business Informatics CDER, U.S. FDA
Amy Malla, Review Management, CBER, U.S. FDA
Geneva Branch

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THE DO’S AND DON’TS OF DATA SUBMISSION
CDER Common Data Standards Issues
SDTM Datasets
 SUPPQUAL
 Should not be used as a waste basket
 DM
 Strongly preferred to use additional variables in
Amendment 1
 DS
 EPOCH should be used to distinguish between multiple

disposition events
If DEATH occurs, it should be documented in the last record
with the associated EPOCH
Geneva Branch

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THE DO’S AND DON’TS OF DATA SUBMISSION
CDER Common Data Standards Issues
SDTM Datasets
 AE
 Provide variables for MedDRA hierarchy
 Sponsors should include all AEs, not only the
one caused by the study treatment
 AESOC = MedDRA-defined, primary mapped
SOC
 AEBODSYS = SOC used for analysis
Geneva Branch

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THE DO’S AND DON’TS OF DATA SUBMISSION
CDER Common Data Standards Issues
SDTM Datasets
 Custom Domains
 Only to be used for data that does not fit in a
published domain
 LB
 Ideal filesize < 400 megabytes
 Larger files should be split according to LBCAT,
LBSCAT; Nonsplit dataset should also be
included
 Discuss with your review division
Geneva Branch

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THE DO’S AND DON’TS OF DATA SUBMISSION
CDER Common Data Standards Issues
SDTM Datasets
 Permissible variables that CDER expects to see
 --BLFL (LB, VS, EG, Pharmacokinetics, Microbiology)
 EPOCH
 --DY and --STDY in SE and Findings
 No imputations allowed
 Dates in ISO 8601
 Missing dates are missing dates
 USUBJID
 No leading or trailing spaces allowed
 Should match across all datasets (SDTM, ADaM) on a
character basis
Geneva Branch