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THE DO’S AND DON’TS OF DATA SUBMISSION

Angelo Tinazzi, profile picture
Angelo Tinazzi

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.

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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
Cytel Inc. - Confidential 2 [A. Tinazzi] 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
Cytel Inc. - Confidential 3 [A. Tinazzi] 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
Cytel Inc. - Confidential 4 [A. Tinazzi] 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
Cytel Inc. - Confidential 5 [A. Tinazzi] 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
Cytel Inc. - Confidential 6 [A. Tinazzi] 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
Cytel Inc. - Confidential 7 [A. Tinazzi] 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
Cytel Inc. - Confidential 8 [A. Tinazzi] 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
Cytel Inc. - Confidential 9 [A. Tinazzi] 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
Cytel Inc. - Confidential 10 [A. Tinazzi] 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
Cytel Inc. - Confidential 11 [A. Tinazzi] 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
Cytel Inc. - Confidential 12 [A. Tinazzi] 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
Cytel Inc. - Confidential 13 [A. Tinazzi] 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
Cytel Inc. - Confidential 14 [A. Tinazzi] 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
Cytel Inc. - Confidential 15 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION A World of Clinical Standards - CDISC Geneva Branch A Failed Submission Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
Cytel Inc. - Confidential 16 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION A World of Clinical Standards - CDISC Geneva Branch A Failed Submission Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
Cytel Inc. - Confidential 17 [A. Tinazzi] 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
Cytel Inc. - Confidential 18 [A. Tinazzi] 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
Cytel Inc. - Confidential 19 [A. Tinazzi] 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
Cytel Inc. - Confidential 20 [A. Tinazzi] 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
Cytel Inc. - Confidential 21 [A. Tinazzi] 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
Cytel Inc. - Confidential 22 [A. Tinazzi] 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
Cytel Inc. - Confidential 23 [A. Tinazzi] 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
Cytel Inc. - Confidential 24 [A. Tinazzi] 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
Cytel Inc. - Confidential 25 [A. Tinazzi] 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
Cytel Inc. - Confidential 26 [A. Tinazzi] 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
Cytel Inc. - Confidential 27 [A. Tinazzi] 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
Cytel Inc. - Confidential 28 [A. Tinazzi] 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 )
Cytel Inc. - Confidential 29 [A. Tinazzi] 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
Cytel Inc. - Confidential 30 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION 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
Cytel Inc. - Confidential 31 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION 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
Cytel Inc. - Confidential 32 [A. Tinazzi] 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
Cytel Inc. - Confidential 33 [A. Tinazzi] 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
Cytel Inc. - Confidential 34 [A. Tinazzi] 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
Cytel Inc. - Confidential 35 [A. Tinazzi] 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
Cytel Inc. - Confidential 36 [A. Tinazzi] 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
Cytel Inc. - Confidential 37 [A. Tinazzi] 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
Cytel Inc. - Confidential 38 [A. Tinazzi] 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
Cytel Inc. - Confidential 39 [A. Tinazzi] 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
Cytel Inc. - Confidential 40 [A. Tinazzi] 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
Cytel Inc. - Confidential 41 [A. Tinazzi] 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
Cytel Inc. - Confidential 42 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION Meet the reviewer Geneva Branch A Failed Submission Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
Cytel Inc. - Confidential 43 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION 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»
Cytel Inc. - Confidential 44 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION What Next Geneva Branch A Failed Submission The FDA/PhUSE Collaboration Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
Cytel Inc. - Confidential 45 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION What Next Geneva Branch A Failed Submission The FDA/PhUSE Collaboration Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
Cytel Inc. - Confidential 46 [A. Tinazzi] 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
Cytel Inc. - Confidential 47 [A. Tinazzi] 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
Cytel Inc. - Confidential 48 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION What Next Geneva Branch A Failed Submission Other PhUSE Initiatives Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
Cytel Inc. - Confidential 49 [A. Tinazzi] 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
Cytel Inc. - Confidential 50 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION What Next Geneva Branch A Failed Submission Data Sharing Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
Cytel Inc. - Confidential 51 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION 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
Cytel Inc. - Confidential 52 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION 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
Cytel Inc. - Confidential 53 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION Questions New Geneva offices – November 2012 Geneva Branch
Cytel Inc. - Confidential [A. Tinazzi] 54 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
Cytel Inc. - Confidential [A. Tinazzi] 55 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
Cytel Inc. - Confidential [A. Tinazzi] 56 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
Cytel Inc. - Confidential [A. Tinazzi] 57 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
Cytel Inc. - Confidential [A. Tinazzi] 58 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
Cytel Inc. - Confidential [A. Tinazzi] 59 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
Cytel Inc. - Confidential [A. Tinazzi] 60 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
Cytel Inc. - Confidential [A. Tinazzi] 61 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
Cytel Inc. - Confidential [A. Tinazzi] 62 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
Cytel Inc. - Confidential [A. Tinazzi] 63 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
Cytel Inc. - Confidential [A. Tinazzi] 64 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
Cytel Inc. - Confidential [A. Tinazzi] 65 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

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THE DO’S AND DON’TS OF DATA SUBMISSION

  • 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
  • 2. Cytel Inc. - Confidential 2 [A. Tinazzi] 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
  • 3. Cytel Inc. - Confidential 3 [A. Tinazzi] 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
  • 4. Cytel Inc. - Confidential 4 [A. Tinazzi] 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
  • 5. Cytel Inc. - Confidential 5 [A. Tinazzi] 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
  • 6. Cytel Inc. - Confidential 6 [A. Tinazzi] 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
  • 7. Cytel Inc. - Confidential 7 [A. Tinazzi] 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
  • 8. Cytel Inc. - Confidential 8 [A. Tinazzi] 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
  • 9. Cytel Inc. - Confidential 9 [A. Tinazzi] 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
  • 10. Cytel Inc. - Confidential 10 [A. Tinazzi] 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
  • 11. Cytel Inc. - Confidential 11 [A. Tinazzi] 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
  • 12. Cytel Inc. - Confidential 12 [A. Tinazzi] 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
  • 13. Cytel Inc. - Confidential 13 [A. Tinazzi] 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
  • 14. Cytel Inc. - Confidential 14 [A. Tinazzi] 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
  • 15. Cytel Inc. - Confidential 15 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION A World of Clinical Standards - CDISC Geneva Branch A Failed Submission Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
  • 16. Cytel Inc. - Confidential 16 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION A World of Clinical Standards - CDISC Geneva Branch A Failed Submission Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
  • 17. Cytel Inc. - Confidential 17 [A. Tinazzi] 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
  • 18. Cytel Inc. - Confidential 18 [A. Tinazzi] 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
  • 19. Cytel Inc. - Confidential 19 [A. Tinazzi] 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
  • 20. Cytel Inc. - Confidential 20 [A. Tinazzi] 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
  • 21. Cytel Inc. - Confidential 21 [A. Tinazzi] 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
  • 22. Cytel Inc. - Confidential 22 [A. Tinazzi] 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
  • 23. Cytel Inc. - Confidential 23 [A. Tinazzi] 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
  • 24. Cytel Inc. - Confidential 24 [A. Tinazzi] 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
  • 25. Cytel Inc. - Confidential 25 [A. Tinazzi] 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
  • 26. Cytel Inc. - Confidential 26 [A. Tinazzi] 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
  • 27. Cytel Inc. - Confidential 27 [A. Tinazzi] 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
  • 28. Cytel Inc. - Confidential 28 [A. Tinazzi] 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 )
  • 29. Cytel Inc. - Confidential 29 [A. Tinazzi] 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
  • 30. Cytel Inc. - Confidential 30 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION 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
  • 31. Cytel Inc. - Confidential 31 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION 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
  • 32. Cytel Inc. - Confidential 32 [A. Tinazzi] 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
  • 33. Cytel Inc. - Confidential 33 [A. Tinazzi] 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
  • 34. Cytel Inc. - Confidential 34 [A. Tinazzi] 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
  • 35. Cytel Inc. - Confidential 35 [A. Tinazzi] 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
  • 36. Cytel Inc. - Confidential 36 [A. Tinazzi] 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
  • 37. Cytel Inc. - Confidential 37 [A. Tinazzi] 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
  • 38. Cytel Inc. - Confidential 38 [A. Tinazzi] 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
  • 39. Cytel Inc. - Confidential 39 [A. Tinazzi] 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
  • 40. Cytel Inc. - Confidential 40 [A. Tinazzi] 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
  • 41. Cytel Inc. - Confidential 41 [A. Tinazzi] 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
  • 42. Cytel Inc. - Confidential 42 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION Meet the reviewer Geneva Branch A Failed Submission Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
  • 43. Cytel Inc. - Confidential 43 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION 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»
  • 44. Cytel Inc. - Confidential 44 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION What Next Geneva Branch A Failed Submission The FDA/PhUSE Collaboration Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
  • 45. Cytel Inc. - Confidential 45 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION What Next Geneva Branch A Failed Submission The FDA/PhUSE Collaboration Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
  • 46. Cytel Inc. - Confidential 46 [A. Tinazzi] 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
  • 47. Cytel Inc. - Confidential 47 [A. Tinazzi] 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
  • 48. Cytel Inc. - Confidential 48 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION What Next Geneva Branch A Failed Submission Other PhUSE Initiatives Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
  • 49. Cytel Inc. - Confidential 49 [A. Tinazzi] 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
  • 50. Cytel Inc. - Confidential 50 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION What Next Geneva Branch A Failed Submission Data Sharing Agencies A world of Standards eCTD Rules Meet the reviewer What Next Conclusions
  • 51. Cytel Inc. - Confidential 51 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION 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
  • 52. Cytel Inc. - Confidential 52 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION 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
  • 53. Cytel Inc. - Confidential 53 [A. Tinazzi] THE DO’S AND DON’TS OF DATA SUBMISSION Questions New Geneva offices – November 2012 Geneva Branch
  • 54. Cytel Inc. - Confidential [A. Tinazzi] 54 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
  • 55. Cytel Inc. - Confidential [A. Tinazzi] 55 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
  • 56. Cytel Inc. - Confidential [A. Tinazzi] 56 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
  • 57. Cytel Inc. - Confidential [A. Tinazzi] 57 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
  • 58. Cytel Inc. - Confidential [A. Tinazzi] 58 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
  • 59. Cytel Inc. - Confidential [A. Tinazzi] 59 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
  • 60. Cytel Inc. - Confidential [A. Tinazzi] 60 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
  • 61. Cytel Inc. - Confidential [A. Tinazzi] 61 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
  • 62. Cytel Inc. - Confidential [A. Tinazzi] 62 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
  • 63. Cytel Inc. - Confidential [A. Tinazzi] 63 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
  • 64. Cytel Inc. - Confidential [A. Tinazzi] 64 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
  • 65. Cytel Inc. - Confidential [A. Tinazzi] 65 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