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This document summarizes Angelo Tinazzi and Cedric Marchand's experience submitting clinical trial data to the FDA using CDISC standards. It describes their recent submission, including standards used, current status, and interaction with FDA reviewers. It also discusses requirements for electronic submissions and FDA feedback received from a test submission, including suggestions for SDTM content and define.xml. The presentation aims to help others in properly preparing FDA submissions using CDISC standards.

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Geneva Branch Cytel Inc. - Confidential - 1 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] An FDA Submission Experience Using the CDISC Standards RG04 Angelo Tinazzi, Cedric Marchand Cytel Inc. Geneva – Switzerland angelo.tinazzi@cytel.com cedric.marchand@cytel.com
Geneva Branch Cytel Inc. - Confidential - 2 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Disclaimer The content of this presentation represents our personal experience with this particular submission with this specific sponsor on a specific indication Although some of the slides contain information coming from existing requirements, such as CDISC standards and FDA guidance, they represent our experience of applying standards and interacting with the FDA Topic and timing of subission, as well as reviewer ‘preferences’, are important factors to consider when submitting data to FDA
Geneva Branch Cytel Inc. - Confidential - 3 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] News SOMEWHERE, Mass., Oct. 06, 2017 Wonderful Company, Inc. (Nasdaq:WOND) today announced that the U.S. Food and Drug Administration (FDA) approved GoodDrug™, the first and only …..
Geneva Branch Cytel Inc. - Confidential - 4 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Key Requirements Our Recent Submission Interaction with the Reviewer Test (Mock) Submission Conclusions Agenda
Geneva Branch Cytel Inc. - Confidential - 5 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Key Requirements (1) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions Electronic submission Use of Standards Technical Details
Geneva Branch Cytel Inc. - Confidential - 6 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Key Requirements (2) How? (cont) http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards  FDA Standards Catalog  Exchange Format  i.e. SAS XPT, XML, PDF, ASCII  Regulatory Applications  Electronic Common Techinical Document (eCTD)  Data Exchange Format  SDTM, ADAM (Clinical Study Datasets)  Define.xml (Study Data Definition)  Terminology Standards  CDISC Controlled Terminology  MedDRA, WHO-DD  CDISC Metadata Submission Guidelines Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 7 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Key Requirements (3) …and do not forget Portable Document Format (PDF) Specifications  Use of fonts, colors  PDF properties eCTD Specifications for Validation Criteria i.e. Filename  lowercase, letters, digits and ‘-’ (hyphen)  Max 64 chars Technical Rejection Criteria  SDTM TS, DM mandatory  ADSL mandatory for ADaM package Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 8 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Key Requirements (4) Electronic Commot Technical Document Specifications - http://estri.ich.org/eCTD/eCTD_Specification_v3_2_2.pdf FDA Data Technical Conformance Guide - http://www.fda.gov/downloads/ForIndustry/DataStandards/StudyDataStandards/UCM384744.pdf ADaM Analysis Datasets and Programs Non ADaM Analysis Datasets and Programs Non-SDTM Tabulation Datasets SDTM Tabulation Datasets Other datasets i.e. look-up datasets ISS/ISE Pooling Folders More details in the backup slides eCTD m5 folder Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 9 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] FDA CTR Limitation to 1000 characters length See recent discussion in Linkedin « CDISC-SDTM experts » See also P21 forum https://www.pinnacle21.com/forum/dd0086-maximum- length-1000-characters-data-attributes Key Requirements (5) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 10 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] FDA CTR Limitation to 1000 characters length (cont) Additional Documents provided linked in define.xml or appendix of the reviewer guide i.e. ADRG Key Requirements (6) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions Issue solved but validation criteria to be updated
Geneva Branch Cytel Inc. - Confidential - 11 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Our Recent Submission (1)  Indication: Pain in a « specific » indication  Scope of Work: FDA NDA submission  ISS: Integrated Summary of Safety  ISE: Integrated Summary of Efficacy  Nr. Of studies: 6  3 only ISE: 1018 Randomized patients  6 ISS: 1155 Randomized patients  Cytel involved in SDTM Migration, Phase II/III pivotal studies analysis, ISS/ISE Pooling and Analysis, Data Submission Package, Gives Advice  Sponsor Interact with FDA and responsibe for final package preparation, Takes Decisions Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 12 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Our Recent Submission (2) Standards Used  SDTM Ig 3.2 + cSDRG (Study Data Reviewer Guide) as per latest PhUSE template  ADAM Ig 1.0 + ADRG (Analysis Data Reviewer Guide) as per latest PhUSE template  Define.xml 2.0 + ADaM and Output programs details provided in the ADRG i.e. SAS proc used, source ADAM dataset, selection (i.e. PARAMCD to be used, way of selecting correct records to be analysed, etc.) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 13 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Our Recent Submission (3) Current Status  Submitted in December 2016  1st set of FDA Feedback in February 2017  « Looping » through sponsor exploratory analyses and FDA additional requests 8-10 Months Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 14 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (1) Pre-NDA meeting Sponsor request Month: 0 3 4 10* FDA Written Preliminary Feedback / Answers Meeting Submission Formal Meetings Between the FDA and Sponsors or Applicants https://www.fda.gov/downloads/drugs/guidances/ucm153222.pdf Anticipate Items / Questions you would like to discuss during the meeting with regards to the application * These are from our experience i.e. they are not standard FDA timeline Ongoing interaction Test submission Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 15 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (2) Pre-NDA Meeting – Example of Questions Does the FDA concur with the Sponsor’s plan regarding the composition and format of the clinical data submission for the XXXXXXX NDA? Do not use «Open Question», always propose solutions and ask for confirmation (seek for an agreeement) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 16 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (3) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions Sponsor Question: « Does the Division agree with Wonderful Company’s proposed plan for submitting standardized electronic datasets for data from the clinical development program? » FDA Answer: «In addition we have the following comments regarding the dataset:»
Geneva Branch Cytel Inc. - Confidential - 17 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (3) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 18 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (3) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 19 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (3) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 20 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (3) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 21 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (3) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions « The integrated safety dataset must include the following variables: a. Unique patient identifier b. ….. i. Flag indicating whether or not the event occurred within 30 days of discontinuation »
Geneva Branch Cytel Inc. - Confidential - 22 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (4) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) More feedback  Replication » of potential covariates / subgroup variables in all ADaM datasets i.e. RACE, SEX  make a clear plan in the SAP  MedDRA Version to be used in the pooled ISS  SMQ Proposal for further safety investigation Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 23 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (5) Pre-NDA Meeting By site investigator listings for investigator on-sites inspections purpose FDA OSI Webinar: Overview of information Requested by CDER OSI…… https://collaboration.fda.gov/p44198603 Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 24 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (6) More details in the backup slides OSI Packages. What you need to know for your next NDA or BLS Submission - PharmaSUG 2015 Pre-NDA Meeting By site investigator listings for investigator on-sites inspections (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 25 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Test (Mock) Submission (1) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions  Techinical questions (i.e. CDISC) sent via email to the eData Group  Test submission with one study (full eCTD package)  SDTM and ADaM datasets  Good Technical Feedback and Advice
Geneva Branch Cytel Inc. - Confidential - 26 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017]  FDA run the Pinnacle21 Community tool  No SDRG/ADRG review  Some good suggestions for define.xml  Supplemental Qualifier and Value Level Metadata (VLM) Origin Mismatch « When origins for all VLM items within one variable are not the same an Origin for Variable should have a missing value with all details provided on VLM » i.e. SUPPCM VLMs origin vs CM.QVAL origin Test (Mock) Submission (2) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 27 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017]  Suggestions on SDTM Content i.e. RACE=‘OTHER’ in DM domain  « CAMBODIAN » should be represented as « ASIAN »  « NATIVE CANADIAN » should be represented as « AMERICAN INDIAN OR ALASKA NATIVE »  « MIDDLE EAST » and « PALESTINIAN » should be represented as « WHITE » - DM.RACE with CDISC CT - Original value in SUPPCM Test (Mock) Submission (3) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 28 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017]  Other technical issues  Some SDTM discrepancies. Most of them corrected meanwhile i.e. Use of YN terminology vs Y terminology  Advice on ”Permissible variable with missing value for all records” NO ACTION variables kept for output programming purpose and explained in the cSDRG More details in the backup slides Test (Mock) Submission (4) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 29 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Conclusions  (for sponsor) Adopt CDISC ASAP, starting with CDASH ‘Lost in Traceability’ has a cost!!!  (for sponsor) Vendor Surveillance, make sure they do it right and consistently  Try to influence your sponsor or your regulatory department (educate)  Plan ahead, clarify with the reviewer any doubts/special situations  Reviewer Preferences  A lot of documentation effort (cSDRG and ADRG) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
Geneva Branch Cytel Inc. - Confidential - 30 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Angelo Tinazzi – Director – Standards, Systems, CDISC Consulting (CDISC E3C Member) angelo.tinazzi@cytel.com Cedric Marchand – Executive Director – Global Head of Statistical Programming cedric.marchand@cytel.com Cytel, Shaping the Future of Drug Development
Geneva Branch Cytel Inc. - Confidential - 31 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] References  «Lost» in Traceability, from SDTM to ADaM …. finally Analysis Results Metadata» A. Tinazzi, CDISC Europe Interchange 2016  «Looking for SDTM migration specialist » A. Tinazzi, PhUSE 2014  «Interpreting CDISC ADaM IG through Users Interpretation» A. Tinazzi, PhUSE 2013  «The do’s and don’ts of Data Submission» A. Tinazzi, BIAS 2013  «Traceability: Plan Ahead for Future Needs» – S. Minjoe, T. Petrowitsch, PhUSE 2014  «Traceability and Data Flow PhUSE-CSS WG» http://www.phusewiki.org/wiki/index.php?title=Traceability_and_ Data_Flow  «Summary of Traceability References PhUSE-CSS Wiki Page» http://www.phusewiki.org/wiki/index.php?title=Summary_of_Trac eability_References
Geneva Branch Cytel Inc. - Confidential - 32 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] An FDA Submission Experience Using the CDISC Standards The purpose of this presentation is to share an FDA submission experience using the CDISC standards. After introducing the key current requirements when submitting data sets to the FDA, either SDTM or ADaM, some key learning will be shared. This includes, for example, interaction with the FDA and the additional requests we received as well as the feedback after performing the test submission.
Geneva Branch Cytel Inc. - Confidential - 33 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] The Data Package (2)  Clinical Study Datasets  Study Data Definition  Supportive Documents to Study Data Definition  Data Validation Reports Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 34 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] The Data Package (3) ../m5/datasets/006/tabulations/sdtm Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 35 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] The Data Package (4) ../m5/datasets/ISE/analysis/adam/datasets ../m5/datasets/ISS/analysis/misc Lookup datasets used in the creation of some ADAM datasets Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 36 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] The Data Package (5) Submitting Programs FDA Requirements Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 37 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] The Data Package (6) ../m5/datasets/ISE/analysis/adam/programs ADaM Programs Tables Programs Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 38 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping – Gap Analysis (1)  Initiated prior to commencing migration activities  How to perform gap analysis  Itemization and evaluation of files to support migration activities  Document inventory  Study documents  CDISC Standards  Company Standards / Company Implementation Guidance  Validate sample CRF fields versus source data  External data requirements e.g. central labs or local labs  Comparison of protocol amendments/versions against CRF versions  Clarifies the scope and challenges of migration activities  Identifies differences in data collection formats Introduction My Recent Submission The Data Package Interaction with FDA SDTM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 39 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping – Gap Analysis (2) Documents and Data Inventory Introduction My Recent Submission The Data Package Interaction with FDA SDTM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 40 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with FDA – Pre (1) Type of Meetings - Type A: a meeting needed to help an otherwise stalled product development program proceed i.e. meetings for discussing clinical holds - Type B: pre-IND, end-of-Ph-I, pre-NDA - Type C: any non Type A / Type B meeting regarding the development and review of a product Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions Formal Meetings Between the FDA and Sponsors or Applicants https://www.fda.gov/downloads/drugs/guidances/ucm153222.pdf
Geneva Branch Cytel Inc. - Confidential - 41 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with FDA – Pre (2) Pre-NDA– Data Submission Strategy Additional Details/requirements - Lab with Normal Ranges - Use WHO drug dictionary - Unique coding / nomenclature for Placebo across studies - Common variables across datasets - Case summaries and CRF for all SAEs, deaths and Discontinuation due to Adverse Events Introduction My Recent Submission The Data Package Interaction with FDA SDTM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 42 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with FDA – Pre (3) Pre-NDA– Data Submission Strategy Additional Details/requirements (cont) - Site Level Dataset (optional for now!) - For Pivotal studies: - Number of subjects screened for each site by site - Number of subjects randomized for each site by site, if appropriate - Number of subjects treated who prematurely discontinued for each site by site Introduction My Recent Submission The Data Package Interaction with FDA SDTM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 43 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with FDA – Pre (5) Pre-NDA – Data Submission Strategy Additional feedback Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 44 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with FDA – Pre (6) Pre-NDA– Data Submission Strategy Additional feedback Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 45 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping (1)  Relatively Easy to handle  A lot of Questionnaires  Pain Assessment  WOMAC  GIC  SF-12  KOOS  Most of them are not covered by any CDISC standards  Easy treatment exposure - one single day injection Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 46 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping Adverse Events Issue with seriousness criteria not properly collected in old studies  FDA « wants » that  re-collected retrospectively from safety surveillance dept and integrated in SDTM NOT ALWAYS RECCOMENDED AND FEASIBLE A Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions More details in the backup slides
Geneva Branch Cytel Inc. - Confidential - 47 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping (2) Be Harmonized - visit/visitnum - Cosistent terminology - Consistent QNAM in SUPPxx Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 48 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping (4) Study Population i.e. per protocol  Not fully derivable  Peer review process  Integrated from xls files into SUPPDM (possible with 3.2) and DV SDTM IG 3.3 Draft Study Population not in SDTM, only in ADaM!!! Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 49 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping (5)  Unscheduled VISITNUM and EPOCH derivation  IG gives some suggestion to when unplanned visits to mantain chronology  PhUSE CSS provides some more detailed approaches for VISTNUM and EPOCH derivation  Be aware deriving VISITNUM for unscheduled visits can be very time-consuming http://www.phusewiki.org/wiki/index.php?title=VISITNUM_and_EPOCH Introduction My Recent Submission The Data Package Interaction with FDA SDTM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 50 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Pooling for ISS and ISE  Done in ADaM from single study SDTMs  Adverse Events Medical Coding Up-versioning Required  Ref FDA Study Data Technical Conformance Guidance  In SDTM (no guidance in Ig) vs ADaM (examples of multiple versions handling in OCCDS) A Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions FDA Feedback “If the version that is to be used for the ISS is different than versions that were used for individual study data or study reports, it is important to provide a table that lists all events whose preferred term or hierarchy mapping changed when the data was converted from one MedDRA version to another. This will be very helpful for understanding discrepancies that may appear when comparing individual study reports/data with the ISS study report/data”
Geneva Branch Cytel Inc. - Confidential - 51 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Pooling Issues – Differences with CSR (1) Be Transparent make use of Reviewer Guide http://www.phusewiki.org/wiki/in dex.php?title=Study_Data_Revi ewer%27s_Guide http://www.phusewiki.org/wiki/index.php?titl e=Analysis_Data_Reviewer%27s_Guide A Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 52 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Pooling Issues – Differences with CSR (2) Different MedDRA Version A Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 53 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Pooling Issues – Differences with CSR (3) Different MedDRA Version Bridge Document provided in appendix A Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions More details in the backup slides
Geneva Branch Cytel Inc. - Confidential - 54 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Validation Issues Data-issues of locked studies  Documented in the Reviewer Guide  « Hard-coding » agreed with sponsor when correction was obvious i.e. start>end but clearly wrong year or confirmation obtained from source document without unlocking data (!! « A Note to File » is needed in the programming documentation and mentioned in the RG) A Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions More details in the backup slides
Geneva Branch Cytel Inc. - Confidential - 55 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Pooling Issues – Differences with CSR (4) Different visits windowing in the ISE Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 56 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping – CDISC Traceability  3 studies migrated prospectively  perfect CDISC traceaility SDTM  ADaM  Analysis Outputs  CSR  3 studies migrated post CSR  traceability issue Traceability Issues mentioned in FDA Study Data Technical Conformance Guidance Original CSR based on legacy raw and analysis data with post SDTM conversion for ISS/ISE pooling Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
Geneva Branch Cytel Inc. - Confidential - 57 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Validation Issues (1) Performed with Pinnacle 21 Several ‘false’ positives  RG  Validation checks for BDS for non-BDS ADaM  Extensible Controlled Terminology Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions

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regulatory.pptx

  • 1.
    Geneva Branch Cytel Inc.- Confidential - 1 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] An FDA Submission Experience Using the CDISC Standards RG04 Angelo Tinazzi, Cedric Marchand Cytel Inc. Geneva – Switzerland angelo.tinazzi@cytel.com cedric.marchand@cytel.com
  • 2.
    Geneva Branch Cytel Inc.- Confidential - 2 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Disclaimer The content of this presentation represents our personal experience with this particular submission with this specific sponsor on a specific indication Although some of the slides contain information coming from existing requirements, such as CDISC standards and FDA guidance, they represent our experience of applying standards and interacting with the FDA Topic and timing of subission, as well as reviewer ‘preferences’, are important factors to consider when submitting data to FDA
  • 3.
    Geneva Branch Cytel Inc.- Confidential - 3 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] News SOMEWHERE, Mass., Oct. 06, 2017 Wonderful Company, Inc. (Nasdaq:WOND) today announced that the U.S. Food and Drug Administration (FDA) approved GoodDrug™, the first and only …..
  • 4.
    Geneva Branch Cytel Inc.- Confidential - 4 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Key Requirements Our Recent Submission Interaction with the Reviewer Test (Mock) Submission Conclusions Agenda
  • 5.
    Geneva Branch Cytel Inc.- Confidential - 5 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Key Requirements (1) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions Electronic submission Use of Standards Technical Details
  • 6.
    Geneva Branch Cytel Inc.- Confidential - 6 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Key Requirements (2) How? (cont) http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards  FDA Standards Catalog  Exchange Format  i.e. SAS XPT, XML, PDF, ASCII  Regulatory Applications  Electronic Common Techinical Document (eCTD)  Data Exchange Format  SDTM, ADAM (Clinical Study Datasets)  Define.xml (Study Data Definition)  Terminology Standards  CDISC Controlled Terminology  MedDRA, WHO-DD  CDISC Metadata Submission Guidelines Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 7.
    Geneva Branch Cytel Inc.- Confidential - 7 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Key Requirements (3) …and do not forget Portable Document Format (PDF) Specifications  Use of fonts, colors  PDF properties eCTD Specifications for Validation Criteria i.e. Filename  lowercase, letters, digits and ‘-’ (hyphen)  Max 64 chars Technical Rejection Criteria  SDTM TS, DM mandatory  ADSL mandatory for ADaM package Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 8.
    Geneva Branch Cytel Inc.- Confidential - 8 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Key Requirements (4) Electronic Commot Technical Document Specifications - http://estri.ich.org/eCTD/eCTD_Specification_v3_2_2.pdf FDA Data Technical Conformance Guide - http://www.fda.gov/downloads/ForIndustry/DataStandards/StudyDataStandards/UCM384744.pdf ADaM Analysis Datasets and Programs Non ADaM Analysis Datasets and Programs Non-SDTM Tabulation Datasets SDTM Tabulation Datasets Other datasets i.e. look-up datasets ISS/ISE Pooling Folders More details in the backup slides eCTD m5 folder Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 9.
    Geneva Branch Cytel Inc.- Confidential - 9 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] FDA CTR Limitation to 1000 characters length See recent discussion in Linkedin « CDISC-SDTM experts » See also P21 forum https://www.pinnacle21.com/forum/dd0086-maximum- length-1000-characters-data-attributes Key Requirements (5) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 10.
    Geneva Branch Cytel Inc.- Confidential - 10 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] FDA CTR Limitation to 1000 characters length (cont) Additional Documents provided linked in define.xml or appendix of the reviewer guide i.e. ADRG Key Requirements (6) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions Issue solved but validation criteria to be updated
  • 11.
    Geneva Branch Cytel Inc.- Confidential - 11 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Our Recent Submission (1)  Indication: Pain in a « specific » indication  Scope of Work: FDA NDA submission  ISS: Integrated Summary of Safety  ISE: Integrated Summary of Efficacy  Nr. Of studies: 6  3 only ISE: 1018 Randomized patients  6 ISS: 1155 Randomized patients  Cytel involved in SDTM Migration, Phase II/III pivotal studies analysis, ISS/ISE Pooling and Analysis, Data Submission Package, Gives Advice  Sponsor Interact with FDA and responsibe for final package preparation, Takes Decisions Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 12.
    Geneva Branch Cytel Inc.- Confidential - 12 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Our Recent Submission (2) Standards Used  SDTM Ig 3.2 + cSDRG (Study Data Reviewer Guide) as per latest PhUSE template  ADAM Ig 1.0 + ADRG (Analysis Data Reviewer Guide) as per latest PhUSE template  Define.xml 2.0 + ADaM and Output programs details provided in the ADRG i.e. SAS proc used, source ADAM dataset, selection (i.e. PARAMCD to be used, way of selecting correct records to be analysed, etc.) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 13.
    Geneva Branch Cytel Inc.- Confidential - 13 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Our Recent Submission (3) Current Status  Submitted in December 2016  1st set of FDA Feedback in February 2017  « Looping » through sponsor exploratory analyses and FDA additional requests 8-10 Months Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 14.
    Geneva Branch Cytel Inc.- Confidential - 14 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (1) Pre-NDA meeting Sponsor request Month: 0 3 4 10* FDA Written Preliminary Feedback / Answers Meeting Submission Formal Meetings Between the FDA and Sponsors or Applicants https://www.fda.gov/downloads/drugs/guidances/ucm153222.pdf Anticipate Items / Questions you would like to discuss during the meeting with regards to the application * These are from our experience i.e. they are not standard FDA timeline Ongoing interaction Test submission Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 15.
    Geneva Branch Cytel Inc.- Confidential - 15 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (2) Pre-NDA Meeting – Example of Questions Does the FDA concur with the Sponsor’s plan regarding the composition and format of the clinical data submission for the XXXXXXX NDA? Do not use «Open Question», always propose solutions and ask for confirmation (seek for an agreeement) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 16.
    Geneva Branch Cytel Inc.- Confidential - 16 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (3) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions Sponsor Question: « Does the Division agree with Wonderful Company’s proposed plan for submitting standardized electronic datasets for data from the clinical development program? » FDA Answer: «In addition we have the following comments regarding the dataset:»
  • 17.
    Geneva Branch Cytel Inc.- Confidential - 17 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (3) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 18.
    Geneva Branch Cytel Inc.- Confidential - 18 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (3) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 19.
    Geneva Branch Cytel Inc.- Confidential - 19 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (3) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 20.
    Geneva Branch Cytel Inc.- Confidential - 20 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (3) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 21.
    Geneva Branch Cytel Inc.- Confidential - 21 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (3) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions « The integrated safety dataset must include the following variables: a. Unique patient identifier b. ….. i. Flag indicating whether or not the event occurred within 30 days of discontinuation »
  • 22.
    Geneva Branch Cytel Inc.- Confidential - 22 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (4) Pre-NDA Meeting - Data Submission Strategy FDA Feedback (cont) More feedback  Replication » of potential covariates / subgroup variables in all ADaM datasets i.e. RACE, SEX  make a clear plan in the SAP  MedDRA Version to be used in the pooled ISS  SMQ Proposal for further safety investigation Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 23.
    Geneva Branch Cytel Inc.- Confidential - 23 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (5) Pre-NDA Meeting By site investigator listings for investigator on-sites inspections purpose FDA OSI Webinar: Overview of information Requested by CDER OSI…… https://collaboration.fda.gov/p44198603 Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 24.
    Geneva Branch Cytel Inc.- Confidential - 24 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with the Reviewer (6) More details in the backup slides OSI Packages. What you need to know for your next NDA or BLS Submission - PharmaSUG 2015 Pre-NDA Meeting By site investigator listings for investigator on-sites inspections (cont) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 25.
    Geneva Branch Cytel Inc.- Confidential - 25 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Test (Mock) Submission (1) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions  Techinical questions (i.e. CDISC) sent via email to the eData Group  Test submission with one study (full eCTD package)  SDTM and ADaM datasets  Good Technical Feedback and Advice
  • 26.
    Geneva Branch Cytel Inc.- Confidential - 26 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017]  FDA run the Pinnacle21 Community tool  No SDRG/ADRG review  Some good suggestions for define.xml  Supplemental Qualifier and Value Level Metadata (VLM) Origin Mismatch « When origins for all VLM items within one variable are not the same an Origin for Variable should have a missing value with all details provided on VLM » i.e. SUPPCM VLMs origin vs CM.QVAL origin Test (Mock) Submission (2) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 27.
    Geneva Branch Cytel Inc.- Confidential - 27 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017]  Suggestions on SDTM Content i.e. RACE=‘OTHER’ in DM domain  « CAMBODIAN » should be represented as « ASIAN »  « NATIVE CANADIAN » should be represented as « AMERICAN INDIAN OR ALASKA NATIVE »  « MIDDLE EAST » and « PALESTINIAN » should be represented as « WHITE » - DM.RACE with CDISC CT - Original value in SUPPCM Test (Mock) Submission (3) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 28.
    Geneva Branch Cytel Inc.- Confidential - 28 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017]  Other technical issues  Some SDTM discrepancies. Most of them corrected meanwhile i.e. Use of YN terminology vs Y terminology  Advice on ”Permissible variable with missing value for all records” NO ACTION variables kept for output programming purpose and explained in the cSDRG More details in the backup slides Test (Mock) Submission (4) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 29.
    Geneva Branch Cytel Inc.- Confidential - 29 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Conclusions  (for sponsor) Adopt CDISC ASAP, starting with CDASH ‘Lost in Traceability’ has a cost!!!  (for sponsor) Vendor Surveillance, make sure they do it right and consistently  Try to influence your sponsor or your regulatory department (educate)  Plan ahead, clarify with the reviewer any doubts/special situations  Reviewer Preferences  A lot of documentation effort (cSDRG and ADRG) Key Requirements Our Recent Submission Interaction with Reviewer Test Submission Conclusions
  • 30.
    Geneva Branch Cytel Inc.- Confidential - 30 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Angelo Tinazzi – Director – Standards, Systems, CDISC Consulting (CDISC E3C Member) angelo.tinazzi@cytel.com Cedric Marchand – Executive Director – Global Head of Statistical Programming cedric.marchand@cytel.com Cytel, Shaping the Future of Drug Development
  • 31.
    Geneva Branch Cytel Inc.- Confidential - 31 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] References  «Lost» in Traceability, from SDTM to ADaM …. finally Analysis Results Metadata» A. Tinazzi, CDISC Europe Interchange 2016  «Looking for SDTM migration specialist » A. Tinazzi, PhUSE 2014  «Interpreting CDISC ADaM IG through Users Interpretation» A. Tinazzi, PhUSE 2013  «The do’s and don’ts of Data Submission» A. Tinazzi, BIAS 2013  «Traceability: Plan Ahead for Future Needs» – S. Minjoe, T. Petrowitsch, PhUSE 2014  «Traceability and Data Flow PhUSE-CSS WG» http://www.phusewiki.org/wiki/index.php?title=Traceability_and_ Data_Flow  «Summary of Traceability References PhUSE-CSS Wiki Page» http://www.phusewiki.org/wiki/index.php?title=Summary_of_Trac eability_References
  • 32.
    Geneva Branch Cytel Inc.- Confidential - 32 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] An FDA Submission Experience Using the CDISC Standards The purpose of this presentation is to share an FDA submission experience using the CDISC standards. After introducing the key current requirements when submitting data sets to the FDA, either SDTM or ADaM, some key learning will be shared. This includes, for example, interaction with the FDA and the additional requests we received as well as the feedback after performing the test submission.
  • 33.
    Geneva Branch Cytel Inc.- Confidential - 33 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] The Data Package (2)  Clinical Study Datasets  Study Data Definition  Supportive Documents to Study Data Definition  Data Validation Reports Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 34.
    Geneva Branch Cytel Inc.- Confidential - 34 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] The Data Package (3) ../m5/datasets/006/tabulations/sdtm Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 35.
    Geneva Branch Cytel Inc.- Confidential - 35 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] The Data Package (4) ../m5/datasets/ISE/analysis/adam/datasets ../m5/datasets/ISS/analysis/misc Lookup datasets used in the creation of some ADAM datasets Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 36.
    Geneva Branch Cytel Inc.- Confidential - 36 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] The Data Package (5) Submitting Programs FDA Requirements Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 37.
    Geneva Branch Cytel Inc.- Confidential - 37 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] The Data Package (6) ../m5/datasets/ISE/analysis/adam/programs ADaM Programs Tables Programs Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 38.
    Geneva Branch Cytel Inc.- Confidential - 38 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping – Gap Analysis (1)  Initiated prior to commencing migration activities  How to perform gap analysis  Itemization and evaluation of files to support migration activities  Document inventory  Study documents  CDISC Standards  Company Standards / Company Implementation Guidance  Validate sample CRF fields versus source data  External data requirements e.g. central labs or local labs  Comparison of protocol amendments/versions against CRF versions  Clarifies the scope and challenges of migration activities  Identifies differences in data collection formats Introduction My Recent Submission The Data Package Interaction with FDA SDTM Pooling Validation Conclusions
  • 39.
    Geneva Branch Cytel Inc.- Confidential - 39 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping – Gap Analysis (2) Documents and Data Inventory Introduction My Recent Submission The Data Package Interaction with FDA SDTM Pooling Validation Conclusions
  • 40.
    Geneva Branch Cytel Inc.- Confidential - 40 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with FDA – Pre (1) Type of Meetings - Type A: a meeting needed to help an otherwise stalled product development program proceed i.e. meetings for discussing clinical holds - Type B: pre-IND, end-of-Ph-I, pre-NDA - Type C: any non Type A / Type B meeting regarding the development and review of a product Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions Formal Meetings Between the FDA and Sponsors or Applicants https://www.fda.gov/downloads/drugs/guidances/ucm153222.pdf
  • 41.
    Geneva Branch Cytel Inc.- Confidential - 41 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with FDA – Pre (2) Pre-NDA– Data Submission Strategy Additional Details/requirements - Lab with Normal Ranges - Use WHO drug dictionary - Unique coding / nomenclature for Placebo across studies - Common variables across datasets - Case summaries and CRF for all SAEs, deaths and Discontinuation due to Adverse Events Introduction My Recent Submission The Data Package Interaction with FDA SDTM Pooling Validation Conclusions
  • 42.
    Geneva Branch Cytel Inc.- Confidential - 42 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with FDA – Pre (3) Pre-NDA– Data Submission Strategy Additional Details/requirements (cont) - Site Level Dataset (optional for now!) - For Pivotal studies: - Number of subjects screened for each site by site - Number of subjects randomized for each site by site, if appropriate - Number of subjects treated who prematurely discontinued for each site by site Introduction My Recent Submission The Data Package Interaction with FDA SDTM Pooling Validation Conclusions
  • 43.
    Geneva Branch Cytel Inc.- Confidential - 43 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with FDA – Pre (5) Pre-NDA – Data Submission Strategy Additional feedback Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 44.
    Geneva Branch Cytel Inc.- Confidential - 44 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Interaction with FDA – Pre (6) Pre-NDA– Data Submission Strategy Additional feedback Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 45.
    Geneva Branch Cytel Inc.- Confidential - 45 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping (1)  Relatively Easy to handle  A lot of Questionnaires  Pain Assessment  WOMAC  GIC  SF-12  KOOS  Most of them are not covered by any CDISC standards  Easy treatment exposure - one single day injection Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 46.
    Geneva Branch Cytel Inc.- Confidential - 46 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping Adverse Events Issue with seriousness criteria not properly collected in old studies  FDA « wants » that  re-collected retrospectively from safety surveillance dept and integrated in SDTM NOT ALWAYS RECCOMENDED AND FEASIBLE A Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions More details in the backup slides
  • 47.
    Geneva Branch Cytel Inc.- Confidential - 47 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping (2) Be Harmonized - visit/visitnum - Cosistent terminology - Consistent QNAM in SUPPxx Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 48.
    Geneva Branch Cytel Inc.- Confidential - 48 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping (4) Study Population i.e. per protocol  Not fully derivable  Peer review process  Integrated from xls files into SUPPDM (possible with 3.2) and DV SDTM IG 3.3 Draft Study Population not in SDTM, only in ADaM!!! Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 49.
    Geneva Branch Cytel Inc.- Confidential - 49 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping (5)  Unscheduled VISITNUM and EPOCH derivation  IG gives some suggestion to when unplanned visits to mantain chronology  PhUSE CSS provides some more detailed approaches for VISTNUM and EPOCH derivation  Be aware deriving VISITNUM for unscheduled visits can be very time-consuming http://www.phusewiki.org/wiki/index.php?title=VISITNUM_and_EPOCH Introduction My Recent Submission The Data Package Interaction with FDA SDTM Pooling Validation Conclusions
  • 50.
    Geneva Branch Cytel Inc.- Confidential - 50 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Pooling for ISS and ISE  Done in ADaM from single study SDTMs  Adverse Events Medical Coding Up-versioning Required  Ref FDA Study Data Technical Conformance Guidance  In SDTM (no guidance in Ig) vs ADaM (examples of multiple versions handling in OCCDS) A Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions FDA Feedback “If the version that is to be used for the ISS is different than versions that were used for individual study data or study reports, it is important to provide a table that lists all events whose preferred term or hierarchy mapping changed when the data was converted from one MedDRA version to another. This will be very helpful for understanding discrepancies that may appear when comparing individual study reports/data with the ISS study report/data”
  • 51.
    Geneva Branch Cytel Inc.- Confidential - 51 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Pooling Issues – Differences with CSR (1) Be Transparent make use of Reviewer Guide http://www.phusewiki.org/wiki/in dex.php?title=Study_Data_Revi ewer%27s_Guide http://www.phusewiki.org/wiki/index.php?titl e=Analysis_Data_Reviewer%27s_Guide A Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 52.
    Geneva Branch Cytel Inc.- Confidential - 52 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Pooling Issues – Differences with CSR (2) Different MedDRA Version A Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 53.
    Geneva Branch Cytel Inc.- Confidential - 53 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Pooling Issues – Differences with CSR (3) Different MedDRA Version Bridge Document provided in appendix A Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions More details in the backup slides
  • 54.
    Geneva Branch Cytel Inc.- Confidential - 54 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Validation Issues Data-issues of locked studies  Documented in the Reviewer Guide  « Hard-coding » agreed with sponsor when correction was obvious i.e. start>end but clearly wrong year or confirmation obtained from source document without unlocking data (!! « A Note to File » is needed in the programming documentation and mentioned in the RG) A Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions More details in the backup slides
  • 55.
    Geneva Branch Cytel Inc.- Confidential - 55 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Pooling Issues – Differences with CSR (4) Different visits windowing in the ISE Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 56.
    Geneva Branch Cytel Inc.- Confidential - 56 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] SDTM Mapping – CDISC Traceability  3 studies migrated prospectively  perfect CDISC traceaility SDTM  ADaM  Analysis Outputs  CSR  3 studies migrated post CSR  traceability issue Traceability Issues mentioned in FDA Study Data Technical Conformance Guidance Original CSR based on legacy raw and analysis data with post SDTM conversion for ISS/ISE pooling Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions
  • 57.
    Geneva Branch Cytel Inc.- Confidential - 57 - [A. Tinazzi C. Marchand – An FDA Submission Experience Using the CDISC Standards – PhUSE 2017 Edinburgh 08-11 October 2017] Validation Issues (1) Performed with Pinnacle 21 Several ‘false’ positives  RG  Validation checks for BDS for non-BDS ADaM  Extensible Controlled Terminology Introduction My Recent Submission The Data Package Interaction with FDA SDTM ADaM Pooling Validation Conclusions

Editor's Notes

  • #6 The parent guidance in this series of documents is “Guidance for Industry: Providing Regulatory Submissions in Electronic Format – Submissions Under Section 745A(a) of the Federal Food, Drug and Cosmetic Act” [9]. The primary objective of this guidance is to affirm that, as soon as December 2016, you will need to submit most if not all INDs, NDAs, ANDAs and BLAs electronically as opposed to filing on paper. The 2nd guidance document in succession is “Guidance for Industry: Providing Regulatory Submissions in Electronic Format – Standardized Study Data” [10]. Following on to the requirement that most if not all submissions must be electronic, this guidance goes on to state that studies initiated in the relatively near future must utilize specific data standards for the collection, analysis and delivery of clinical and non-clinical trial data and results as endorsed by the FDA as documented in the Data Standards Catalog [12]. This requirement kicks in for studies that would support an NDA, ANDA or BLA on the 2 year anniversary of the guidance document becoming final (December 17, 2016) and one year later for INDs. Two noteworthy observations: SDTCG provides specifications, recommendations, general considerations on how to submit standardized study data using FDA-supported1 data standards located in the FDA Data Standards Catalog (Standards Catalog).2
  • #10 FDA Clinical Trial Repository (CTR) software currently has a maximum length of 100 chars for data attributes in define.xml (VARCHAR(1000)). Janus CTR is the standard FDA infrastructure that support receipt, validation, storage, easy access and analysis of study data
  • #15 Pre-NDA Type C Meeting Seek for agreement on strategy for clinical efficacy and safety in support to the registration i.e. type of trials i.e. efficacy endpoints i.e. pooling strategy ISS and ISE SAP feedback Indirect i.e. through the sponsor Example of questions
  • #24 FDA uses onsite inspections to ensure that clinical investigators, sponsors, and Institutional Review Boards (IRB) comply with FDA regulations while developing investigational drugs or biologics. Medical reviewers, who are responsible for approving or disapproving a product, consult with BIMO reviewers to choose which clinical trial sites to inspect. ● Part I: General study related information and specific Clinical Investigator Information ● Part II: Subject Level Data Listings by Site ● Part III: Summary Level Clinical Site Data (SLCS)
  • #26 •Technical Questions on Data Standardization •eData Group for questions on CDISC standards via email •Questions/answers independent of any submission •Mock (Test) Submission •Submission of (live) sample CDISC data in eCTD structure •Assessment by FDA eSub/eData groups: Validation Report, Additional Feedback •No information passed on to review division Key facts from a couple of test submisison Any guidance to check!!!!
  • #27 At this stage they made use of the Reviewer Guide ‘only’ to check for standards used i.e. SDTM Ig Version
  • #30 Special situation i.e. extension studies