DIA EDM Webinar eCTD Update - December 5, 2013 Mark Gray

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DIA EDM Webinar eCTD Update - December 5, 2013 Mark Gray
DIA EDM Webinar
                            eCTD Update

                            December 5, 2013

Mark Gray
Director, Division of Data Management Services & Solutions
(CDER/OSP/OBI)                                               1
DIA EDM Webinar eCTD Update - December 5, 2013 Mark Gray
Disclaimer
•   Views expressed in this presentation are those of the speaker and
    not necessarily of the Food and Drug Administration.
•   The views and opinions expressed in the following PowerPoint
    slides are those of the individual presenter and should not be
    attributed to Drug Information Association, Inc. (“DIA”), its directors,
    officers, employees, volunteers, members, chapters, councils,
    Special Interest Area Communities or affiliates, or any organization
    with which the presenter is employed or affiliated.
•   These PowerPoint slides are the intellectual property of the
    individual presenter and are protected under the copyright laws of
    the United States of America and other countries. Used by
    permission. All rights reserved. Drug Information Association, DIA
    and DIA logo are registered trademarks or trademarks of Drug
    Information Association Inc. All other trademarks are the property of
    their respective owners.

                                                                           2
DIA EDM Webinar eCTD Update - December 5, 2013 Mark Gray
Agenda
• eCTD Guidance

• eCTD Metrics

• Module 1 Update

• eCTD v4.0

                          3
DIA EDM Webinar eCTD Update - December 5, 2013 Mark Gray
eCTD Guidance
• Food and Drug Administration Safety and
  Innovation Act (FDASIA) of 2012
  » Gives FDA the authority to require electronic
    submissions for certain application types after
    issuance of final guidance
  » Reauthorizes PDUFA and established GDUFA

• PDUFA and GDUFA will require electronic
  submissions in the eCTD format, after issuance
  of final guidance

                                                      4
DIA EDM Webinar eCTD Update - December 5, 2013 Mark Gray
PDUFA V eCTD Guidance Process
• PDUFA Performance Goals
   – Issue guidance for NDA, BLA, and IND submissions in the eCTD
     format
      • Issue Draft Guidance by December 31, 2012
      • Based on eCTD v3.2.2
      • Issue final eCTD guidance no later than 12 months after public
        comment period

• Implementation
   – NDA and BLA – 24 months after publication of final guidance
   – Commercial INDs – 36 months after publication of final guidance

• NOTE: FDA will follow this process to meet the GDUFA
  eCTD submission requirements
                                                                         5
DIA EDM Webinar eCTD Update - December 5, 2013 Mark Gray
eCTD Guidance Status
•   Issued guidance for NDA, BLA, ANDA and IND requiring
    submissions in the eCTD format
     – FR Notice Published 1/3/2013
     – Draft eCTD Guidance
     – PDUFA V process: Issue final eCTD guidance no later than 12 months
       after public comment period
         • Comment period closed March 4, 2013

•   Plan is to reissue the eCTD draft guidance
     – Based on internal discussions and updated Interpretation of FDASIA
     – Still based on eCTD v3.2.2
     – Issued updated draft eCTD guidance in early 2014
•   Updated implementation target – Mandatory eCTD submission
     – NDA, BLA, and ANDA: Late 2016 – early 2017
     – Commercial INDs: Late 2017 – early 2018

                                                                            6
DIA EDM Webinar eCTD Update - December 5, 2013 Mark Gray
FDA eCTD Submissions
                   as of October 4th, 2013

Application           Number of               Number of
  Type               Applications             Sequences
   IND                               5,582          264,813
   NDA                               2,507           85,856
  ANDA                               8,645           85,308
   BLA                                  266          24,383
    MF                               1,931            9,782
FDA Internal                            834           1,570
   Total                            19,771          471,705
                                                              7
DIA EDM Webinar eCTD Update - December 5, 2013 Mark Gray
8
DIA EDM Webinar eCTD Update - December 5, 2013 Mark Gray
CDER Investigational New Drugs

                            FY2009   FY2010   FY2011 FY2012     FY2013
IND Research                12,863   14,816   16,039   14,767    15,176
IND Commercial              74,163   77,402   77,013   76,419    76,672
IND Total                   87,026   92,218   93,052   91,186    91,848
IND Research Electronic        456      721    1,185    1,477     1,841
IND Commercial Electronic   24,913   36,794   48,116   55,108    60,722
IND Electronic Total        25,369   37,515   49,301   56,585    62,563
IND Electronic %            29.15%   40.68% 52.98%     62.05%   68.12%
IND Research eCTD              326      595    1,008    1,324     1,595
IND Commercial eCTD         24,448   36,219   47,564   54,677    60,259
IND eCTD                    24,774   36,814   48,572   56,001    61,854
eCTD % of Total             28.47%   39.92% 52.20%     61.41%   67.34%
eCTD % of Electronic        97.66%   98.13% 98.52%     98.97%   98.87%
                                                                          9
DIA EDM Webinar eCTD Update - December 5, 2013 Mark Gray
10
CDER New Drug Applications

                           FY2009    FY2010   FY2011   FY2012   FY2013
NDA Total                  22,148    22,443   23,254   23,746    22,822
NDA Electronic             13,297    15,497   17,396   18,694    18,563
NDA Electronic %           60.04%    69.05%   74.81%   78.72%   81.34%
NDA eCTD                    11,146   14,007   15,937   17,682    17,747
NDA eCTD % of Total        50.33%    62.41%   68.53%   74.46%   77.76%
NDA eCTD % of Electronic   83.82%    90.39%   91.61%   94.59%   95.60%

                                                                          11
12
CDER Abbreviated New Drug Applications

                            FY2009    FY2010    FY2011   FY2012   FY2013
ANDA Total                  29,554    19,408    22,186   26,514    42,687
ANDA Electronic              11,045    11,637   16,554   20,639    29,521
ANDA Electronic %           37.38%    59.96%    74.61%   77.84%   69.16%
ANDA eCTD                    6,341      8,113   12,915   16,314    23,295
ANDA eCTD % of Total        21.46%    41.80%    58.21%   61.53%   54.57%
ANDA eCTD % of Electronic   57.41%    69.72%    78.02%   79.04%   78.91%

                                                                            13
14
FDA eCTD M1 Update
• Update includes;
   – Additional submission metadata to facilitate submission
     processing
       • Contact information (e.g., regulatory, technical)
       • Application cross references
       • Supplement effective date type (PAS, CBE-0, CBE-30)
   – Submission Numbering
       • Application Type – Application Number
       • Submission Type – Submission Id
       • Submission Sub-Type – Sequence Number
   – Flexibility to reduce possibility of DTD changes
       • Attribute values (e.g. submission-type, submission-sub-type)
   – Functionality for grouped submissions
   – Updated M1 Headings and Hierarchy
       • Major changes to 1.15 Promotional Material
       • Heading attributes for 1.1 Forms and 1.15
                                                                        15
FDA eCTD M1 Update
•   Implementation
    – CDER will accept eCTD promotional submissions when the M1 update
      is implemented
    – After transitioning an application to the new M1, that application must
      continue to use the new M1 DTD
    – Errata (4/2/2013) and FR Notice (8/26/2013)
        • Additional attributes on 1.15.2.1 Material
             – Material Id – Applicant’s id code
             – Issue Date – Date of initial dissemination or publication
        • Added promotional labeling contact type
    – Target Implementation Update
        • New implementation date is 4th quarter 2014
             – Mitigate risk based on number of software/system updates required
             – Will give 30 days advance notice to industry

•   Impact on eCTD v3.2.2 electronic submission requirement
    – Both the current M1 DTD (v2.01) and updated M1 DTD (v3.2) will be
      accepted
                                                                                   16
eCTD v4.0 Project
•   Implementation of the Health Level Seven (HL7) Regulated Product
    Submission (RPS) standard
    – HL7 exchange standard that can be used for the submission of any
      regulated product
    – Medical Device (IMDRF) participation in the RPS project

•   What does this mean?
    – eCTD v4 will use the RPS exchange message
    – eCTD v4 is a subset of RPS implemented specifically for human
      pharmaceuticals
    – Huh? Ah, what?
        • The eCTD headings and hierarchy are not changing
        • Think of it as a technology upgrade with some enhancements

                                                                         17
RPS Message Capabilities (Summary)
•   Submission metadata (e.g, Application Type and Number)
     – Has additional metadata to facilitate processing of the submissions

•   Life-cycle functionality (active, inactive)
     – Ability to life-cycle one to one, one to many, many to one
•   Correct/modify Keywords
•   Handles bundled/global/grouped submissions
•   File Reuse – Submit file once and cross-reference
•   Ability to identify file types (e.g, SDTM dataset) for additional processing
•   Standardize submission format/structure by application type (e.g. NDA, DMF)
•   Two-way communication
     – The regulatory authority can use RPS to send correspondence to the submitter
•   ICH and Regional requirements
     – Additional product information
     – Multi-regulator submissions
     – ICH and regional requirements incorporated into one model                      18
eCTD v4.0 ICH Schedule
• 2012 / 2013 Accomplishments
   –   DSTU Ballot
   –   Test case development & testing
   –   Controlled vocabulary development
   –   Draft Implementation Guides
        • Draft eCTD v4 ICH Implementation Guide
        • Draft Regional Module 1 Implementation Guides

• ICH M8 Step 2 for Testing
   –   http://estri.ich.org/new-eCTD/index.htm
   –   Draft ICH Implementation Guide
   –   Lessons Learnt
   –   Draft ICH Code List
   –   Schema Files
   –   Links to Regional eCTD v4.0 web pages
                                                          19
eCTD v4.0 ICH Schedule
•   RPS Normative Ballot (September 2013)
     – Reviewing HL7 RPS ballot comments
     – Will require a re-ballot
     – ISO approval process starts after a successful HL7 normative ballot
•   Testing (January 2014 – June 2014)
•   Update/Finalize Implementation Guides (May 2013 – November 2014)
•   ICH Step 2 Signoff (November 2014)
•   ICH Step 3 Comment & Reconciliation (November 2014 – June 2015)
•   ICH Step 4 Signoff (November 2015)
     – Update Step 2 Implementation Guide (June 2015 – November 2015)
•   Based on current Implementation schedule: FDA begin receiving eCTD v4.0
    submissions in 2016
     – Most likely will start with a pilot
     – Requires guidance update
•   FDA is required to issue revised final guidance before mandating eCTD    20
    v4.0
eCTD Website
– eCTD Guidance
– eCTD Headings & Hierarchy
– Specifications
   •   ICH (Modules 2 – 5)
   •   FDA Module 1
   •   eCTD Validation Criteria
   •   Related Specifications (e.g., PDF, Transmission, Study Data)
– eCTD supportive files (DTD, stylesheet, valid values)
– Link to the eCTD Updated Module 1 information

eCTD Website address:
  http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Elect
  ronicSubmissions/ucm153574.htm

                                                                                    21
Quality and Product Data
                  Standards
                   DIA EDM and ERS/eCTD Webinar
                           December 5, 2013

Jared Lantzy
Data Management Solutions Team
Division of Data Management Services and Solutions
                                                     22
(FDA/CDER/OSP/OBI)
Disclaimer
•   Views expressed in this presentation are those of the speaker and
    not necessarily of the Food and Drug Administration.
•   The views and opinions expressed in the following PowerPoint
    slides are those of the individual presenter and should not be
    attributed to Drug Information Association, Inc. (“DIA”), its directors,
    officers, employees, volunteers, members, chapters, councils,
    Special Interest Area Communities or affiliates, or any organization
    with which the presenter is employed or affiliated.
•   These PowerPoint slides are the intellectual property of the
    individual presenter and are protected under the copyright laws of
    the United States of America and other countries. Used by
    permission. All rights reserved. Drug Information Association, DIA
    and DIA logo are registered trademarks or trademarks of Drug
    Information Association Inc. All other trademarks are the property of
    their respective owners.

                                                                          23
A Clarification
        “Quality” Data Standards

Not referring to the condition or worth of the
data, but the standardization of data normally
found in review documents in Module 3
(Quality) of the eCTD

                                                 24
Agenda
•   The Problem
•   The Solution
•   Current CDER Projects
•   Next Steps

                            25
The Problem
• An immense amount of data is submitted
  in each and every CDER application
  – Unstructured, in the text of documents
  – Module 1 – Regional
  – Module 3 – Quality

                                             26
The Problem (2)
• Manual data entry into systems
• Multiple systems
  – Same data, different functions
• Data is not linked in a useful way

                                       27
The Solution
• Data standards for Quality data
  – Structured data that can be properly linked to
    all its applications, sponsors, products,
    substances, and facilities
• eSubmission of structured data with the
  application
• Automated import into CDER’s master
  data system
                                                 28
Current CDER Projects
• CDER master data management
  – New systems, processes, and procedures to
    combine new and existing data from within
    CDER to create and maintain a single,
    accurate source of data for CDER systems to
    reference and consume
  – For example, provide the ability to quickly link
    a specific drug substance to all applications
    and products using that substance
                                                   29
Current CDER Projects (2)
• Facility information
  – 356h Form
  – GDUFA Facility Self-ID (SPL)
  – Standardized Establishment Information List
    (SPL)
• Product and Substance Information
  – Drug Registation and Listing (SPL)
  – ISO IDMP Standards (SPL)
                                                  30
Next Steps
• Standards development within CDER,
  ICH, and ISO
  – IDMP is early in the ISO standardization
    process with industry partner support

                                               31
Next Steps (2)
• Writing and issuing draft guidance in
  accordance with FDASIA
  – Draft guidances are published for comment,
    revised, made final, and then another 24
    months before submission can be required
  – FDA will be requiring certain types of
    electronic submissions AND standardized
    data within the application

                                                 32
Industry Questions
•   IDMP looking at the overarching standard, given the complexity
    what is how mandated, how soon and realize the extensive impacts
    on the sponsors, vendors and user community? Takeaway w/
    standards and timelines
     – Does FDA realize the implications to industry
•   IDMP; would like to see the current timelines and know current
    thinking of SPL technology and if there will be a link with IDMP
•   Electronic application forms and filled out form, do you think FDA
    will be moving towards that the information will be captured in the
    Admin information in eCTD instead of the same information being
    captured in the FDA PDF forms? Why have information on the
    metadata being captured since it is duplicative
•   What are people doing to ignore FDA forms security?
                                                                      33
Validation
• FDA Forms
  – Use the FDA Forms as downloaded from our
    forms website, without changing any settings
    or adding or removing any additional security
    features.
  – Our validation tool will ignore PDF security
    errors for the proper unmodified FDA Forms
    located in the proper section of the eCTD

                                                    34
Validation (2)
• FDA Forms (cont.)
  – If you are unable to use digital signatures,
    submit an unsigned fillable form with the form
    number as the file name (e.g. 356h.pdf or
    1571.pdf)
  – Submit your signed scanned form as signed­
    form.pdf, ensuring you don’t inlcude the form
    number in the file name

                                                 35
Validation (3)
• PDF Errors
  – Font embedding
    • The intent is to ensure the review division can
      access all the information in your submission
    • If you stick to the “standard fonts” there is no need
      to embed, these fonts are always available on
      reviewer PCs
    • If you use “non-standard fonts” you should fully
      embed the font.

                                                          36
Validation (4)
• PDF Errors
  – Font embedding (cont.)
    • We are not rejecting submissions with medium
      error 5005 Non standard font (not embedded)
    • If we are unable to access information because
      your non-standard font is not embedded, we will
      contact you to resubmit the affected document(s)
       – This could affect a review clock if the scope of
         documents is wide enough!

                                                            37
Study Data Standards Update

           Ron Fitzmartin, PhD, MBA
          Office of Strategic Programs
    Center for Drug Evaluation and Research
         Food and Drug Administration

            EDM and ERS Webinar:
          FDA Update/Progress Report

               December 5, 2013
                                              38
Disclaimer
•   Views expressed in this presentation are those of the speaker and
    not necessarily of the Food and Drug Administration.
•   The views and opinions expressed in the following PowerPoint
    slides are those of the individual presenter and should not be
    attributed to Drug Information Association, Inc. (“DIA”), its directors,
    officers, employees, volunteers, members, chapters, councils,
    Special Interest Area Communities or affiliates, or any organization
    with which the presenter is employed or affiliated.
•   These PowerPoint slides are the intellectual property of the
    individual presenter and are protected under the copyright laws of
    the United States of America and other countries. Used by
    permission. All rights reserved. Drug Information Association, DIA
    and DIA logo are registered trademarks or trademarks of Drug
    Information Association Inc. All other trademarks are the property of
    their respective owners.

                                                                          39
Topics
• CDER-CBER Study Data Standards Statement

• Path to Required Data Standards

• Guidance and Notice Update

• Therapeutic Area Standards Development

                                             40
                                                  40
Study Data Standards
for Regulatory Submissions

                             41
                                  41
De-Constructing the Statement
“FDA recognizes the investment made by sponsors over the
 past decade to develop the expertise and infrastructure to
                 utilize CDISC standards.”

  Pharma’s challenges have never been greater. R&D spend
     increases 5 percent annually, while output of NMEs
           approved has dropped by ~22 percent.
                                         --Accenture, 2013

Companies have invested staff, $$$ and time in processes,
          technology and CDISC Standards.
                                                              42
                                                                   42
43
     43
De-Constructing the Statement
PDUFA V states “that FDA will develop guidance for industry
  on the use of CDISC data standards for the electronic
        submission of study data in applications.”

• Draft Guidance on Providing Regulatory Submissions in
  Electronic Format: Standardized Study Data
• Draft Study Data Technical Conformance Guide
• Draft Therapeutic Area Data Standards Initiative Plan
• Notice on Pilot Evaluation of CDISC SDS XML

                                                          44
                                                               44
De-Constructing the Statement
“FDA envisions a semantically interoperable and sustainable
 submission environment that serves both regulated clinical
                research and health care.”

  “Shared Health And Clinical Research Electronic Library
 (SHARE) is expected to dramatically improve integration
   among CDISC foundational standards and controlled
  terminologies, and support greater interoperability with
                       healthcare.”
                              --CDISC, October, 2013
                                                             45
                                                                  45
De-Constructing the Statement
   “FDA does not foresee the replacement of CDISC
  standards for study data and will not implement new
approaches without public input on the cost and utility of
                   those approaches.”

  It has taken decades for Industry & FDA to
  get to this point with study data standards,
         specifically CDISC standards!

                                                             46
                                                                  46
FDASIA* Reauthorizes PDUFA V
  “…develop                                         “… periodically publish

  standardized clinical                             final guidance specifying
                                       PDUFA V
  data terminology                    Performance      the completed data
                                       Goals- XII
  through open                                      standards, formats, and

  standards                                         terminologies that

  development                                       sponsors must use to

  organizations (i.e.,                              submit data in

  CDISC)”                                           applications.”
                                                                         47
                                                                              47
*FDA Safety And Innovation Act-2012
Path to Required Study Data Standards (1)

                       FDASIA Statute

                               FDASIA
                              eGuidance

   Electronic Submission
    Electronic Submission
          Guidance                          Electronic Submission
      Electronic Regulatory
           Guidance                                Guidance
                                          Electronic Standardized
       Submission (eCTD)
                                           Study Data Guidance
            Guidance

   Binding and Non-Binding                Binding and Non-Binding
  Guidance Requiring eSubs in               Guidance Requiring
         eCTD Format                      Standardized Study Data   48
                                                                         48
Path to Required Study Data Standards (2)

Regulation             FDASIA Statute

Binding                      FDASIA
Guidance                    eGuidance

Non-Binding &         Electronic Standardized
Binding                Study Data Guidance
Guidance
Supported &                             Study Data
                Data Standards                          Technical
Required                                 Technical
                   Catalog          Conformance Guide
                                                        Resources
Standards
                                                              49
                                                                    49
Path to Required Study Data Standards (3)
    Data Standards
       Catalog         Data Standards Catalog

  • Catalog to include supported standards, and
    timing for required standards.

  • Data Standards webpage being re-designed.
        – Easier navigation / access to information.
        – Redundant information removed.
        – Expected to be available when guidances are published.

  • Aligned with Technical Conformance Guide.
                                                                              50
http://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm
Path to Required Study Data Standards (4)
Study Data Technical
Conformance Guide      Study Data Technical Conformance Guide

• Provides recommendations for submission of standardized
  study data.

• Complements and assists in the interaction between
  sponsors and divisions.
      •    It will not replace the need for sponsors to communicate with review
           divisions.

• When final, will replace the Common Data Standards
  Issues and Study Data Specifications documents.
                                                                          51
Path to Required Study Data Standards (6)

• Submission of standardized study data will be
  required
  – According to a phased-in schedule, but not before…

     • Federal Register publication of the…
         1.   Draft FDASIA & Revised draft eStudy Data guidances, for public
              comment.

         2.   Final FDASIA guidance & Final eStudy Data guidance.

  – Final eStudy Data Guidance will specify a phased-in
    schedule
     • No earlier than 24 months after final guidance for certain NDAs,
       BLAs, ANDAs.                                                  52
Guidance / Notice Update (1)

                              • Draft in Development
   Draft FDASIA Guidance      • Anticipate FR Publish: FY14
           Revised            •   Draft Published February 2012
 Draft eStudy Data Guidance   •   Revised Draft in Clearance
                              •   Anticipate FR Publish: FY14
    Study Data Technical      •   Draft in Clearance
    Conformance Guide         •   Anticipate FR Publish: FY14

                                                                  53
                                                                       53
Guidance / Notice Update (2)

FR Notice: Therapeutic Area         •   Published - October 2013
Standards Initiative Project Plan

FR Notice: Pilot Project to
                                    • Published November 27, 2013
Evaluate Alternative for Study
Data Transport

                                                                    54
                                                                         54
Collaboration to Develop
                 Therapeutic Area Data Standards

        Public*                                                                      Private
   American College of
      Cardiology
 Alzheimer’s Association                         joint                            Biopharma
   Bill & Melinda Gates                       partnership
         Foundation
                                                                                   Industry
     PKD Foundation

         One Mind
*Sample list

    Academia*                                                                   Government*
                                                                                National Institutes of
     Duke University                                                                    Health
                                                 active                        National Cancer Institute
 University of Wisconsin                      participants
                                                                                National Institute of
 University of Pittsburgh                                                      Neurological Disorders
                                                                                    and Stroke
 Wake Forest University                                                          Office of National
                                                                                    Coordinator
 *Sample list               Coalition for Accelerating Standards & Therapies   *Sample list
                                                                                                     55
CFAST Project Stages & FDA’s Role

• Scientific &            • FDA       • FDA     • FDA Testing /
  Technical                 Divisio     Divisio   Acceptance
  Input                     n           n       • Guidance
                            Expert      Expert
• Planning /                Review      Review
  Prioritization
                                                        56
• Initial Expert
  Review
FDA Process for TA Requirements

                               Requirements        TA Standard
         Plan &                                                        Guidance /
                                 Review &          Acceptance           Policy
         Scoping                Acceptance           Testing

   • Interviews             • Requirement      •      Evaluate         • Update
   • Review                   s report                acceptability of      technical
     Internal                 review and              TA standards          documents,
     documents                acceptance              for use in            as needed
   • Requirements:                                    submissions      • Issue
      -Primary,                                   • Ensure                  Federal
                                                      reviewers’            Register
      -Secondary,                                     readiness to          Notice
      -Covariates,                                    use
      -Exploratory                                    standardized
                                                      data
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirem    57
ents/ElectronicSubmissions/UCM297093.pdf
FDA and CFAST Progress to Date
%
        ~59 TAs
                   % of TAs published & in CFAST
                  proposal, planning & development
                                stages

                                                          58
                       http://www.cdisc.org/therapeutic        58
Thank You

        Ron Fitzmartin
ronald.fitzmartin@fda.hhs.gov

  Data Standards Questions
   cder-edata@fda.hhs.gov
   cber.cdisc@fda.hhs.gov
                                59
DIA EDM Webinar

                  Top Ten Issues with Data

Douglas Warfield, Ph.D.
Technical Team Lead
Interdisciplinary Scientist
(CDER/OSP/OBI)
                                                60
Disclaimer
•   Views expressed in this presentation are those of the speaker and
    not necessarily of the Food and Drug Administration.
•   The views and opinions expressed in the following PowerPoint
    slides are those of the individual presenter and should not be
    attributed to Drug Information Association, Inc. (“DIA”), its directors,
    officers, employees, volunteers, members, chapters, councils,
    Special Interest Area Communities or affiliates, or any organization
    with which the presenter is employed or affiliated.
•   These PowerPoint slides are the intellectual property of the
    individual presenter and are protected under the copyright laws of
    the United States of America and other countries. Used by
    permission. All rights reserved. Drug Information Association, DIA
    and DIA logo are registered trademarks or trademarks of Drug
    Information Association Inc. All other trademarks are the property of
    their respective owners.

                                                                          61
Data Top 10 - Two Categories
What and Where                Content
1. Location/Name        1. USUBJID – DM
2. Define - XML & PDF      duplicates
3. ADaM - no.           2. XPTs and File Size
   columns              3. Splitting Datasets
4. Traceability         4. Units of Measure
5. Legacy and           5. Legacy and
   Standardized            Standardized
                                                62
What and Where
                     Naming
                                 Important for
                                  Automated
                                  Processing!
                                     Exact
                                    spelling
                                    of folder
                                     names
Ref: Study Data Specifications
                                                 63
What and Where
                    Placement
                                 Important for
                                  Automated
                                  Processing!
                                     Exact
                                   placemen
                                      t of
                                    folders
Ref: Study Data Specifications
                                                 64
What and Where
         Data Definitions - Defines
                                            Important for
                                   Exact     Reviewer’s
                                 placemen
                                    t of
                                               Content
                                  defines    Navigation
                                                and
                                             Automated
Ref: Study Data Specifications
                                             Processing!
                                                       65
What and Where
           ADaM - Too Many Columns!
                                                         Too many variables, can
 1. Data Definitions of
                                                       affect usability. 50 variables
    domain columns                                                 max.
 2. Columns relevant to                                Some definitions irrelevant
    the domain                                          to the domain/analyses.
 3. Domain dataset file                                More variables per domain,
    size                                                larger dataset file size.
 4. Traceability of                                     Tracing domain variables
                                                       complexity increases as no.
    content                                              of variables increases.

Ref:   Electronic Regulatory Submissions and Review
       Helpful Links, Study Data Standards Resources                              66
What and Where
                                          Traceability!
               eCRF                                Creating Analysis datasets from a source
           (standardized)                          other than SDTM, when standardized data
                                                   (SDTM) is submitted, is problematic for
                                                   some review activities.

               Raw Data*
              (not submitted)
                                                             Analysis

                                                      Standardized Analyses datasets
                                                      should originate from SDTM datasets.
                  SDTM
                                                      Ref:   Electronic Regulatory Submissions and Review
* Raw Data – research data collected in original             Helpful Links, Study Data Standards Resources
           tabular electronic form.                                                                67
What and Where
     Legacy and Standardized!
1. Can sponsors            Yes, consult with review
   submit both?          division prior to submission.

2. Where? Supported       SDS structure supports
   by specifications?    both concurrently for study.

3. Traceability during   Sponsor should plan quick
   transition.           transitions (regs. - PDUFA.)

4. Integrating           Sponsor integrated/pooled
   (pooled, ISS, ISE,      non-standardized and
   etc.)                   standardized dataset
                         placement is problematic.
                                                   68
Content
           USUBJID – DM duplicates
• Demographics datasets (Legacy or Standardized) where the unique
  subject identifier is NOT unique within the dataset, result in
  failures to “load” data for review in several automated review tools.

• Sponsors should expect review divisions to request sponsors
  submit all demographics datasets compliant with the unique
  subject identifier requirement.

• Sponsors and standards organizations should implement protocol
  designs, data collection, and tabulations to ensure the result of
  unique subject identifiers in the demographics datasets submitted
  for review.

Ref:   Electronic Regulatory Submissions and Review
       Helpful Links, Study Data Standards Resources
                                                                    69
Content
                   XPTs and File Size
• Datasets’ size remain a major concern with data submitted.

• However, more sponsors are resizing submissions using the
  maximum column required in the datasets submitted algorithm,
  based on pre-review analyses of submissions.

• Sponsors should expect review divisions to request sponsors to
  resize datasets, when larger datasets (> 1 gigabyte) are submitted
  and resizing does not appear to have been to used.

• Sponsors and standards organizations should develop and
  promote resizing techniques to ensure reduction of datasets
  submitted for review.
Ref:   Electronic Regulatory Submissions and Review
       Helpful Links, Study Data Standards Resources
                                                                  70
Content
                   Splitting Datasets
• Split datasets’ remains a top issue...

• Review tools rely on specific naming of split datasets to
  automatically combine during “load” processing. (e.g. lb01.xpt,
  lb02.xpt, lb03.xpt are combined to lb.xpt in some review tools).

• Sponsors and standards organizations should develop and
  promote splitting techniques to allow direct review based on
  stratified datasets (e.g. labs by test type), while supporting
  concatenation (identical variables structure) for combined
  analyses.

Ref:   Electronic Regulatory Submissions and Review
       Helpful Links, Study Data Standards Resources
                                                                     71
Content
                    Units of Measure
• Units of Measure for all datasets with measurement values (e.g.
  Labs, Vital Signs) remains a top issue with data submitted, related
  to the variability received in units of measure indicated for
  measurements in observations.

• Greater specificity by review divisions is required for measurement
  types and the standardized measurement unit for the submission
  of data for the type.

• Sponsors and standards organizations should develop and
  promote reduction of measurement types and standardized units
  of measure for the review.

 Ref:   Electronic Regulatory Submissions and Review
        Helpful Links, Study Data Standards Resources
                                                                        72
Content
                          Units of Measure - Variability
                                                          Count of
                                                       LBORRESU and                     Total % by
   Dataset     LBTESTCD    LBORRESU     LBSTRESU                     Percent of Total
                                                        LBSTRRESU                          Test
                                                        Combinations
Lab           BILI        mg/dL       umol/L                      464         19.31%
Lab           BILI        umol/L      umol/L                      372         15.48%
Lab           BILI        mg/dL       mg/dL                       257         10.70%       45.49%
Lab           GLUC        mg/dL       mmol/L                      569         20.29%
Lab           GLUC        mmol/L      mmol/L                      461         16.44%
Lab           GLUC        mg/dL       mg/dL                       372         13.26%       49.98%
Lab           WBC         /HPF        /HPF                        353          4.74%
Lab           WBC         x10^3/uL    giga/L                      240          3.22%                 Variabilit
Lab           WBC         G/L         giga/L                      168          2.25%
Lab           WBC         giga/L      giga/L                      162          2.17%       12.38%
                                                                                                         y
Vital Signs   TEMP        C           C                           896         55.24%
Vital Signs   TEMP        F           C                           321         19.79%
Vital Signs   TEMP        F           F                           116          7.15%       82.18%
Vital Signs   WEIGHT      kg          kg                         1456         60.27%
Vital Signs   WEIGHT      LB          kg                          240          9.93%
Vital Signs   WEIGHT      KG          KG                          149          6.17%       76.37%
Vital Signs   SYSBP       mmHg        mmHg                       1531         84.96%       84.96%
Vital Signs   DIABP       mmHg        mmHg                       1531         85.06%       85.06%

 Note: Source: ~115 NDAs with ~920 different studies

                                                                                                           73
Content
         Legacy and Standardized
                              Data submission issue.
1. Conversion to              Sponsor should provide
   standardized data?       rationale and process used.
2. Review of legacy          Limited review processes and
   content.                 tools using less automation in
                            contrast  to standardized
                               IT review              data .
                                          processes and
3. Review of
                                tools using automation
   standardized
                                based on standardized
   content.                    data. Plan for new regs.(
4. Traceability: legacy                 PDUFA.)
                              Standardization (CDISC)
   vs. standardized          includes traceable content
                                   by specifications.
                                                         74
Top Ten Issues with Data
    Topics to Remember
  Data - What and
   Where
  Data- Content
Importance for 21 Century
        Review!
                            75
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