Preparing Data for an FDA Submission - Clinical Data ......FDA Submission SCDMWorkshop2019 Fred Wood Vice President, Consulting Services SDTM and SEND Implementation Advisor •Introduction

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For class attendee use only. DO NOT DUPLICATE 1

Preparing Data for an FDA Submission

SCDM Workshop 2019

Fred WoodVice President, Consulting Services

SDTM and SEND Implementation Advisor

• Introduction and Learning Objectives• Regulatory Basis for Standardized Electronic Data– FDA Guidance Documents and Technical Specifications

• The Data Standards– CDISC Overview– The Role of PhUSE

© 2019 TalentMine All Rights Reserved. 2

Workshop Outline• Beyond The Data– aCRF– Define– SDRG– SDSP– Software Programs

• Traceability• The Process• Preparing for a Submission

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Introduction

• Who am I?• Who are you?

– What functions are represented in this session?– How many years of industry experience?– How many years have you been in your current position?

• Why did you sign up for this workshop?


Learning Objectives

• Understand the regulatory basis for the requirement for electronic data and standardized electronic study data

• Become aware of the specific data standards the agency expects• Recognize that additional documents/files are required to support the submission of study

data


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Food & Drug Administration Safety & Innovation Act (FDASIA)

• Signed into law on July 9, 2012, amending the Food, Drug, and Cosmetic Act• Expanded the FDA’s authority and strengthens the ability to safeguard and advance

public health by:• Gives the authority to collect user fees

• Prescription drug provisions (PDUFA VI)• Medical device provisions (MDUFA IV)• Generic Drug User Fee Amendments/Act of 2012 (GDUFA II)• Biosimilar User Fee Amendments of 2017 (BsUFA II, 2017‐2022)

• Promotes innovation to speed patient access to safe and effective products• Increases stakeholder involvement in FDA processes• Enhances the safety of the drug supply chain

https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/default.htm


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PDUFA Fees

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User Fee Type FY2019 FY 2020Application Fee – Clinical Data Required $2,942,965 $2,588,478Application Fee – No Clinical Data Required $1,471,483 $1,294,239Program Fee $325,424 $309,915

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MDUFA Fees

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User Fee Type Standard Fee Small Business510(k)‡ $11,594 $2,899513(g) $4,603 $2,302PMA, PDP, PMR, BLA $340,995 $85,249De Novo Classification Request $102,299 $25,575Panel‐track Supplement $255,747 $63,937180‐Day Supplement $51,149 $12,787Real‐Time Supplement $23,870 $5,968BLA Efficacy Supplement $340,995 $85,24930‐Day Notice $5,456 $2,728Annual Fee for Periodic Reporting on a Class III device (PMAs, PDPs, and PMRs)

$11,935 $2,984


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GDUFA Fees

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User Fee Type FY 2019 FY 2020ANDA $ 178,799 $ 176,237DMF $ 55,013 $57,795Program Large Size $ 1,862,167 $ 1,661,684

Medium Size $ 744,867 $ 664,674Small Size $ 186,217 $ 166,168


BsUFA Fees

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User Fee Type FY 2019 FY 2020Biosimilar Biological Product Development (BPD) Fee

Initial BPD $ 185,409 $ 117,987Annual BPD $ 185,409 $ 117,987Reactivation $ 370,818 $ 235,975

Application Fee Clinical Data Required $ 1,746,745 $ 1,746,745Clinical Data not Required $ 873,373 $ 873,373

Program Fee $ 304,162 $ 304,162


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PDUFA Reauthorization Performance Goals And Procedures FY 2018-2022 - Data Standards (1)

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Section 5a and b Highlights• “FDA will develop the staff capacity to efficiently review and provide feedback to sponsors on

the readiness of submitted analysis data sets and programs for statistical review.”

• This staff will support pre‐ and post‐submission discussion of standardized datasets and programs

• Staff will “maintain the knowledge of and engage in collaborations about standards models used in the design, analysis and review of clinical and non‐clinical studies.”

• “FDA will improve staff capacity to assist with FDA development and updating of therapeutic area user guides (TAUGs) to include the appropriate content for the analysis data standards used in submission and review.”

J. ENHANCING REGULATORY DECISION TOOLS TO SUPPORT DRUG DEVELOPMENT AND REVIEW5.a. Enhancing Capacity to Support Analysis Data Standards for Product Development and Review

https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM511438.pdf© 2019 TalentMine All Rights Reserved.

PDUFA Reauthorization Performance Goals And Procedures FY 2018-2022 - Data Standards (2)

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• By end of FY 2019, FDA will convene a public workshop to advance the development and application of analysis data standards. This was held on June 12th. Slides can be found here: https://healthpolicy.duke.edu/sites/default/files/atoms/files/ads_master_slide_deck.pdf

• FDA will collaborate with external stakeholders and participate in public workshops held by third parties such as standards development organizations, on development of data standards, processes, documentation and continuous improvement of clinical trials and regulatory science.

• By end of FY 2020, FDA will develop or revise, as appropriate, relevant guidance, MAPPs, SOPPs and training associated with submission and utilization of standardized analysis datasets and programs used in review, and on the processes, procedures, and responsibilities related to the receipt, handling, and documentation of submitted analysis data and programs.

J. ENHANCING REGULATORY DECISION TOOLS TO SUPPORT DRUG DEVELOPMENT AND REVIEW5.c‐e. Enhancing Capacity to Support Analysis Data Standards for Product Development and Review

https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM511438.pdf© 2019 TalentMine All Rights Reserved.

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FDASIA Text on Electronic Submissions

13© 2019 TalentMine All Rights Reserved.

Guidance for Industry: Providing Regulatory Submissions in Electronic Format – Submissions Under Section 745A (a) of the Federal Food Drug, and Cosmetic Act

Guidance for Industry: Providing Regulatory Submissions in Electronic Format – Standardized Study Data

FDA Guidance and Technical Specifications (1)


Data Standards Catalog Study Data Technical Conformance Guide

Guidance for Industry: Product Development Under the Animal Rule

Parent Guidance

Child Guidances

FDA-Specific Validation Rules for SDTM and SEND

Technical Specifications

Guidance for Industry: Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications

Mentions

References

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FDA Guidance Documents (1)



–What is Covered?• Certain INDs• NDAs• ANDAs• Certain BLAs

– Timing: – Guidelines in this document. Specifics in later FR Notice:• NDAs: Studies starting after December 17, 2016• INDs: Studies starting after December 17, 2017

–Other information: • Binding Guidance• Only 6 pages of content• FDA will develop individual guidances to specify the electronic formats for certain submissions.




https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-regulatory-submissions-electronic-format-submissions-under-section-745aa-federal-food-drug

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• Binding Guidance• Repeats what submission are

covered.• Data must be in a format that

the Agency can process, review, and archive.

• References the FDA Data Standards Catalog.

• Describes Exchange Formats• Mentions CDISC CT, MedDRA.• Reiterates dates.




https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-regulatory-submissions-electronic-format-standardized-study-data




• Binding guidance. • Requirement to submit electronically based on eCTD specifications.• A submission that is not in the format(s) described will not be filed or received, unless it has been exempted.

• Reiterates scope of submission types that must follow this guidance.• References Standardized Study Data guidance and Data Standards Catalog.

• Note: The eCTD is the standard format for submitting applications, amendments, supplements, and reports CDER and CBER.

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-regulatory-submissions-electronic-format-certain-human-pharmaceutical-product-applications

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The eCTD Structure


• Module 1 is region specific.

• Modules 2‐5 are intended to be common for all regions.

FDA Online Learning: https://www.accessdata.fda.gov/cder/eCTD/index.htm




Submission Type Final eCTD Guidance Published to FDA website

Date Requirement Begins

NDA ANDA BLA 2015‐05‐05 2017‐05‐05

Commercial IND Master files other than Type III DMFs

2015‐05‐05 2018‐05‐05

Type III DMFs 2015‐05‐05 2019‐05‐05

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FDA Technical Specifications:Data Standards Catalog (1)• Lists the data standards and terminologies that FDA supports for use in regulatory submissions

• Includes dates for:• When support begins and ends• When the requirement begins and ends• The submission of data using standards or terminologies not listed should be discussed in advance.

• Where more than one standard is listed, submitters may choose one.• Updated several times a year


FDA Technical Specifications:Data Standards Catalog (2)Data Exchange Standards

• Regulatory Applications (IND, NDA, ANDA, BLA, master files)

• Post‐Marketing Safety Reporting • Documents• Analysis Program Files• Clinical and Animal Study Datasets• Data Definition Files• Structured Product Labeling

Terminology Standards• CDISC• MedDRA• WHO Drug• UNII• SNOMED


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FDA Technical Specifications:Data Standards Catalog (4)


https://www.fda.gov/downloads/ForIndustry/DataStandards/StudyDataStandards/UCM340684.xlsx

FDA Technical Specifications:Data Standards Catalog (3)


https://www.fda.gov/downloads/ForIndustry/DataStandards/StudyDataStandards/UCM340684.xlsx

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FDA Technical Specifications:Study Data Validation Rule Types

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• The publication of rules by SDOs that assess conformance to their published standards.

• FDA Business and Validator rules to assess that the data support regulatory review and analysis.

• FDA eCTD Technical Rejection Criteria for Study Data that assess conformance.


Study Data TCG 8.2

SDTMIG v3.2 Conformance Rules v1.0


Accessed via https://www.cdisc.org/standards/foundational/sdtmig

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FDA Technical Specifications:Business and Validator Rules

• Business rules describe the business requirements for regulatory review to help ensure that study data is compliant and useful and supports meaningful review and analysis.

• The business rules are accompanied with validator rules that provide detail regarding FDA's assessment of study data for purposes of review and analysis.

• Validator rules assess conformance with the standard.


Study Data TCG Section 8.2.1

FDA Technical Specifications:Business Rules


Accessed via: https://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm

• Help ensure that study data is compliant and useful and supports meaningful review and analysis.

• Many of these are replicated in the Study Data TCG.

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FDA Technical Specifications:Validator Rules


Accessed via: https://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm

A Note on the Validation Process (not in the Study Data TCG)


• Automated validation tools have limitations.• Sponsors should consider a “human” validation.• Automated tools identify many of the most common errors and inconsistencies with the SDTM and SDTMIG, but:– The number of checks is small compared to the number of implementation decisions.– Not every SDTM/SDTMIG convention can be represented in computer‐executable code.

– Some may not provide clear explanations of how to fix errors:• Source‐data vs. data‐conversion issues

– The creativity of humans will always outpace the development of checks to limit that creativity.

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Where Humans Are Needed for Validation/Conformance

• Domain Selection• Supplemental Qualifiers vs. Findings About• Proper use of variables that don’t have CDISC Controlled Terminology• Relating Records• Trial Design and Related Tables


Author reference: https://www.lexjansen.com/pharmasug/2010/CD/CD16.pdf

FDA Technical Specifications:Technical Rejection Criteria (1)


Background• These are eCTD validation criteria.• Originally published in November 2016. Latest is January 2019.• Applies to clinical studies for which .xpt files are being submitted. • Applies to all nonclinical studies.• Effective Date TBD. FDA has not yet published the 90‐day notice.• When a submission is technically rejected, the submission

sequence is not transferred from the FDA Electronic Submission Gateway into the FDA electronic document rooms.

https://www.fda.gov/media/100743/download

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Requirements:• 1734: A Trial Summary dataset (ts.xpt) dataset must be present for each study in

Modules 4 and 5. The study start date, a parameter listed by the FDA in the TCG, determines whether standardized study data is required.

• 1735: The correct STF file‐tags must be used for all standardized datasets in Modules 4 and 5.

• 1736: A Demographics dataset must be submitted for all studies on Modules 4 and 5. For ADaM data, an ADSL dataset and define.xml must be submitted in Module 5.

• 1789: All files in the study section must be in the STF (eCTD study‐tagging file).

eCTD STF: https://www.fda.gov/media/76790/download

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Basics• First Issued in 2014• Replaces the Study Data Specifications (2004‐2012), the CDER Data Standards Check‐List (2011), and

the Common Data Standards Issues documents (2011)• Provides recommendations on how to submit required standardized study data• Is non‐binding, but adherence to the recommendations facilitates regulatory review• Updated at least twice a year, usually in March and October.Contents Overview• Requests a Study Data Standardization Plan (SDSP)• Recommends a Study Data Reviewer’s Guide (SDRG.pdf) “as an integral part”• Requests that datasets have their contents described with complete metadata in the define.xml file• References the FDA Study Data Standards Catalog• References Technical Rejection Criteria for Study Data• Recommends evaluation of study data against conformance (i.e., validation) rules


FDA Technical Specifications:Study Data Technical Conformance Guide (TCG)


1. Introduction2. Planning and Providing Standardized Study Data

• Study Data Standardization Plan• Study Data Reviewer’s Guides

3. Exchange format – Electronic Submissions• XML• SAS xpt

4. Study Data Submission Format – Clinical and Nonclinical• Study Data Tabulation Model• Analysis Data Model• Standard for Exchange of Nonclinical Data• Data Definition Files For SDTM, SEND, And ADaM

5. Therapeutic Area Standards

6. Terminology• CDISC Controlled Terminology• MedDRA• UNII• WHO Drug Global• National Drug File Reference Terminology• SNOMED CT• LOINC

7. Electronic Submission Format• eCTD Specifications

8. Study Data Validation and Traceability

Appendices on Interoperability, Trial Summary Parameters for Submission, CoDEx, Folder Structure

Study Data Technical Conformance Guide Contents


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CDISC AcronymsCDISC Clinical Data Interchange Standards ConsortiumSDTM Study Data Tabulation ModelADaM Analysis Data ModelSEND Standard for the Exchange of Nonclinical DataCDASH Clinical Data Acquisition Standards HarmonizationODM Operational Data ModelLAB Laboratory Data ModelPRM Protocol Representation ModelMSG Metadata Submissions GuidelineBRIDG Biomedical Research Integrated Domain GroupSHARE Shared Health and Clinical Research Electronic Library


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CDISC Foundational Standards:Collection and Tabulation

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• The Study Data Tabulation Model is a standard for the submission of tabulation data. This is data “as collected”. It is the foundation for five implementation guides.

• The Study Data Tabulation Model Implementation Guide is intended to guide the organization, structure, and format of standard clinical trial tabulation datasets.

• Standard for Exchange of Nonclinical Data (SEND) is an implementation of the SDTM standard for nonclinical studies. It specifies a way to collect and present nonclinical data in a consistent format.

• Clinical Data Acquisition Standards Harmonization (CDASH)consists of a set of content standards (element name, definition, and related metadata) for a basic set of global data collection fields (based upon the SDTM) that will support clinical research studies.

ww.cdisc.org

Other CDISC Foundational Standards

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• The Analysis Data Model (ADaM) is a set of guidelines and examples for analysis datasets used to generate the statistical results for submission to a regulatory authority such as FDA. It specifically addresses needs of statistical reviewers.

• The Protocol Representation Model (PRM) provides a standard for planning and designing a research protocol with focus on study characteristics such as study design, eligibility criteria, and requirements from the ClinicalTrials.gov, World Health Organization (WHO) registries, and EudraCT registries. PRM assists in automating CRF creation and EHR configuration to support clinical research and data sharing.

• The Lab Model (LAB) was created for the transfer of lab data from vendors to sponsors. It can be implemented in ASCII, SAS, or XML.

ww.cdisc.org


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Clinical Data Flow and CDISC Standards

Protocol Form SetupData

CaptureData

StorageAnalysis/ Reporting Submission

Protocol Representation

CDASH(Clinical Data Acquisition

Standardization and Harmonization)

SDTMIG (Study Data

Tabulation Model IG)

ADaM (Analysis

Data Model)

SDTM and ADaM

Lab Data

Lab Model


Nonclinical Data Flow and CDISC Standards

Multiple Data Capture Systems

NonclinicalDatabase

Study Report

SEND Datasets

Submission

SENDIG

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SDTMThe Model

SDTMIG SENDIGImplementation Guides

SDTMIG-MD

SDTMIG-PGx

SDTMIG-AP

Implementation Guide

Supplements

SENDIG-DART

SENDIG-AR

The SDTM and Implementation Guides


TAUGs

QRS Supplements

Metadata Submission Guidelines

UserGuides/Other

CoDEx for SEND 3.0

• CDISC SDTM w/ SDTMIG for clinical tabulation datasets• CDISC ADaM w/ ADaMIG for clinical analysis datasets• CDISC SDTM w/ SENDIG for non‐clinical tabulation datasets

Data Standards to Be Used


Study Data TCG, Sections 4.1.1‐ 4.1.3

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Describe:• Names for commonly submitted datasets• Names for commonly used variables (columns)• Extensive harmonized controlled terminology (data

values)• A set of business rules for implementing SDTM concepts

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The SDTM and SEND Implementation Guides


• Verified collected data - In the study database- In electronic transfers (e.g., lab, ECG, and PK data)- Missing values are missing values

• The SDTMIG and the SENDIG do not tell sponsors what to submit.• The sponsor decides what data to collect, based on science and regulation.• Once the determination has been made on the data to be collected, the SDTMIG and SENDIG provide the structure and format.

• SEND datasets will not replace discussions, summaries, or other information in study reports. • No data should be imputed in SDTM datasets (Study Data TCG, Section 4.1.1.2).

SDTM Datasets


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SDTM and SEND Dataset Definitions

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• Variable (Column) Names• Variable Labels• Data Types• Controlled Terminology• Variable Roles• Implementation Advice• Specific Variable (Column) Order


Identifying Information

Lab Test and Category

© 2017 Accenture All Rights Reserved.

SDTM Lab Dataset Example (1)

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Controlled Terminology

(Content)

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Results and Normal Ranges

Lab Name, Specimen, and Timing

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SDTM Lab Dataset Example (2)

Controlled Terminology

(Content)

ADaM Standards• ADaM Standard v2.1• ADaMIG v1.1• ADaM BDS for TTE Analysis v1.0• ADaM OCCS v1.0


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ADaM Datasets• ADaM datasets should be derived from the data contained in the SDTM datasets.• ADaM standard has variables that allow for traceability to SDTM datasets. • To ensure traceability, all SDTM variables utilized for variable derivations in ADaM should be included in the ADaM datasets when practical. Any submission with analysis data should contain an ADSL.


(Study Data TCG Section 4.1.2.2)

Controlled Terminology• The FDA expects sponsors to utilize controlled terminology wherever available.• Sponsors should use the most recent version of the dictionary available at the start of a clinical or nonclinical study.

• A submission of study data should describe (e.g., in the SDSP, SDRG) the impact, if any, of the use of different versions on the study results.

• If a sponsor identifies a concept for which no standard term exists, FDA recommends that the sponsor submit the concept to the appropriate terminology maintenance organization as early as possible to have a new term added to the standard dictionary.


(Study Data TCG, Sections 6.1.2 and 6.1.3).

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CDISC Controlled Terminology (1)

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• Available for SDTM, SEND, CDASH, ADaM, and PRM• Standard values used with data items within CDISC‐defined datasets. • Harmonized with the National Cancer Institute's Enterprise Vocabulary Services (EVS)• Supports the needs of all CDISC foundational standards and all CFAST disease/therapeutic‐area standards.

• Updated quarterly• Available in Excel, text, odm.xml, pdf, html, and OWL/RDF formats• Also includes a CDISC Glossary of clinical‐study terms• New‐term request can be found at https://ncitermform.nci.nih.gov/ncitermform/?version=cdisc




• Codelist metadata in first row (blue)• Extensible means that sponsors can add to the list as long as the concept does

not exist• Codelist Code (Column A) is inherited by all values (Column B)• Each value has its own code (Column A)• Column E contains the Submission Value to be used in the SEND datasets

https://www.cancer.gov/research/resources/terminology/cdisc?redirect=true

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Example of html version:

Main directory: https://evs.nci.nih.gov/ftp1/CDISC/ Link to above display: https://evs.nci.nih.gov/ftp1/CDISC/SDTM/SDTM%20Terminology.html

Controlled Terminology Summary for Tabulation DataData SDTM Location Controlled Terminology

Lab Tests LBLOINC Logical Observation Identifiers and Codes (LOINC)

Adverse Events AETERM MedDRA (Medical Dictionary for Regulatory Activities )

Trial Indication TSPARMCD = INDIC (Trial Indication)TSPARMCD = TDIGRP (Diagnosis Group)

SNOMED (Systematized Nomenclature of Medicine )

Medication Coding CMDECOD, CMCLAS, CMCLASCD WHO Drug Global

Ingredients TSPARMCD = TRTUNII, COMPTRT, CURTRT UNII (Unique Ingredient Identifier)

Pharmacologic Class TSPARMCD.PCLASS MED-RT (Medication Reference Terminology; was NDF-RT prior to June 2018)

Everything Else Variable and Parameter Names and Values CDISC Controlled Terminology

External dictionary usage should be documented both in the data definition file as well as the Trial Summary (TS) domain if using SDTM IG v3.1.2 or greater or SEND IG v3.0 or greater (Study Data TCG, Section 4.1.4.5).


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• Chronic Hepatitis C • Chronic Obstructive Pulmonary Disease (COPD)• Colorectal Cancer • Dyslipidemia • Diabetes• Diabetic Kidney Disease• Duchenne Muscular Dystrophy• Ebola• Huntington’s Disease• Influenza

• Kidney Transplant• Major Depressive Disorder• Malaria• Prostate Cancer• QT Studies• Rheumatoid Arthritis• Schizophrenia• Traumatic Brain Injury• Tuberculosis


Therapeutic-Area Standards Accepted by FDA

Study Data TCG Section 5

CDISC Data Exchange Standards

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• The Operational Data Model (ODM) is a vendor-neutral, platform-independent, XML-based format for interchange and archive of data from clinical trials, including study data, metadata, and administrative data.

• Study/Trial Design Model (SDM) v1.0 allows organizations to provide rigorous, machine-readable, interchangeable descriptions of the designs of their clinical studies, including treatment plans, eligibility and times and events.

• The CDISC define.xml standard is a Study Data Specification. It is a replacement for the traditional define.pdf, allowing much greater flexibility in the metadata describing the submitted data in a machine-readable format.

• Dataset-XML, initially named “StudyDataSet-XML”, is a new standard used to exchange study datasets in an XML format. The purpose of Dataset-XML is to support the interchange of tabular data for clinical research applications using ODM-based XML technologies.

ww.cdisc.org


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• SAS Version 5 Transport files• Column width should be set to the longest data value.• Files should be split if they exceed 5 GB. Both the split files and the original larger dataset should be submitted.

Study Data Exchange Format


Study Data TCG, Section 3.3.1 and 3.3.2

eCTD Folder Structure for Datasets

Study Data TCG Section 7.1

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• Variable and Dataset Names: alphanumeric characters only• Variable and Dataset Labels: special characters are allowed but:– No unbalanced apostrophes (e.g., Parkinson’s)– No unbalanced single or double quotes– No unbalanced parentheses or brackets– No use of “” whatsoever

• It should be noted that CDISC uses only letters, numbers, and underscores.• For legacy studies started on or before December 17, 2016, it is permissible to use the underscore character in variable names and dataset names.

Study Data TCG, Sections 3.3.3 through 3.3.7

Study Data Exchange Content Restrictions


The Role of PhUSE• In 2013, an effort was begun to develop technologies, position papers, and supplemental implementation advice to support and improve the implementation of (CDISC) data standards.

• PhUSE is not developing standards. • FDA is highly involved. • Working Groups were formed


https://www.phusewiki.org/wiki/index.php?title=CSS_Working_Groupshttps://www.phuse.eu/working‐groups

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PhUSE Optimizing the Use of Data Standards WG (1)• Identify specific gaps preventing FDA and industry from optimizing the use of standards and collaborate to close those gaps.

• Current projects:• Best Practices for Data Collection Instructions• Best Practices for Metadata Documentation (define.xml versus reviewer's guide)• CDISC Implementation Primer• Clinical Legacy Data Conversion Plan & Report• Data Reviewer's Guide in XML• Data Standards for Non‐Interventional Studies• Define‐XML V2.0 Completion Guidelines and Stylesheet Recommendations• Industry Experiences Submitting Standardised Study Data


PhUSE Optimizing the Use of Data Standards WG (2)Archived Deliverables– ADRG Completion Guidelines and Examples– nSDRG Completion Guidelines and Template– SDRG Completion, Template, and Examples


https://www.phuse.eu/css‐archive‐deliverables

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Additional PhUSE Working Groups

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Data Transparency Clinical Trials Data Transparency Toolkit

Data De‐identification Toolkit

De‐identification Standards

EMA Policy 0070 Interpretations

GDPR Impact on Data Collection Practices

Policy, Guidance & Materials Reviews

Educating for the Future

Data Engineering Data Science Design Thinking

Emerging Trends & Technologies

Blockchain Technology

Cloud Adoption in the Life Science Industry

Data Visualisation for Clinical Data

Going Translational with Linked Data

Investigating the Use of FHIR in Clinical Research

Key Performance Indicators & Metrics

Machine Learning & Artificial Intelligence

Open Source Technologies in Clinical Research

Real World Evidence

Nonclinical Topics Data Consistency: SEND Datasets and the Study Report

Demystifying Define‐XML Codelists for Nonclinical Studies

Industry SEND Progress Survey

Modeling Endpoints: How to Model Anti‐Drug Antibody Data in Nonclinical Studies

Nonclinical Script Assessment

Nonclinical Study Data Reviewer's Guide

SEND Implementation User Group

SEND Dataset QC Best Practices

Optimizing the Use of Data Standards

Best Practices for Data Collection Instructions

CDISC Implementation Primer

Data Reviewer's Guide in XML

Data Standards for Non‐Interventional Studies

Industry Experiences Submitting Study Data to Regulatory Authorities

Integrated SDTM and ADaM Reviewer's Guide

SDTM ADaM Implementation FAQ

Standard Analyses & Code Sharing

Analyses & Displays White Papers

Best Practices for Quality Control & Validation

Code Sharing (Repository)

Communications, Promotion and Education

GPP in Macro Development

Test Data Factory







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Workshop Outline• Beyond The Data– aCRF– Define.xml– Reviewer’s Guides– SDSP– Software Programs


Annotated Case Report Form(aCRF)• Should be provided as a PDF file named “acrf.pdf”.• Should include all available forms used to collect source data, including treatment assignment

forms.• The text “NOT SUBMITTED” should be annotated onto the aCRF where data are recorded on the

CRF but not submitted, and an explanation for why data was not submitted should appear in the Study Data Reviewer’s Guide.

• Create as a native PDF document. Avoid scanned copies.• Include pages (screens) from any patient reported outcomes devices.

Study Data TCG, Section 4.1.4.6


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Data Definition Files (define.xml)• These are the “Table of Contents” for the submitted datasets.• Provide separate files for SEND, SDTM, and ADaM.• Version 2.0 is preferred.• Provide a printable PDF version (define.pdf) if the define.xml cannot be printed. This was an issue with define.xml v1.0.

(Study Data TCG, Section 4.1.4.5).


Define.xml: Dataset Metadata

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• Every submitted (e.g., tabulation, analysis) dataset is accompanied by information of up to five levels:

– Dataset level

– Variable level

– Value level

– Codelist level

– Derivation level (algorithms used)


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Define.xml: Dataset-Level Metadata (1)


Define.xml: Dataset-Level Metadata (2)


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Define.xml: Variable-Level Metadata (1)




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• Origin or source of each variable — removed from the models, but should be included in the define file. – Assigned: coded terms – Collected: collected data – Derived: age– Protocol: vital signs position– eDT: lab data received electronically



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• Origin or source of each variable — removed from the models, but should be included in the define file.



SDTMIG SENDIGCollectedDerivedAssigned ProtocoleDT

CollectedDerivedOtherNot Available

Define.xml: Value-Level Metadata (1)


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Define.xml: Value-Level Metadata (2)


Define.xml: Codelist-Level Metadata


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Define.xml: Computational Algorithms

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Method Type Description

Algorithm to derive AEENDY Computation AEENDY = AEENDTC -RFSTDTC+1 if AEENDTC is on or after RFSTDTC. AEENDTC - RFSTDTC

if AEENDTC precedes RFSTDTC

Algorithm to derive AESTDY Computation AESTDY = AESTDTC - RFSTDTC+1 if AESTDTC is on or after RFSTDTC. AESTDTC - RFSTDTC

if AESTDTC precedes RFSTDTC

Algorithm to derive the AETRTEM flag Computation AETRTEM = "Y" if Adverse Event was not present prior to the RFSTDTC, or it was present

prior to the RFSTDTC but increased in severity during the treatment period. Null otherwise.

Algorithm to derive AGE Computation Age at Screening Date (Screening Date - Birth date). For the complete algorithm see the

referenced external document.

Algorithm to derive LBBLFL Computation Safety subjects only: LBBLFL = "Y" for last record with non Null LBORRES on or before the

first dose date (RFSTDTC). Null otherwise.

Algorithm to derive LBDY Computation LBDY = LBDTC-RFSTDTC+1 if LBDTC is on or after RFSTDTC. LBDTC - RFSTDTC if LBDTC

precedes RFSTDTC.

Algorithm to derive LBNRIND Computation Reference Range Indicator based upon standard results and ranges.


Study Data Reviewer’s Guide (cSDRG and nSDRG)• Describes any special considerations or directions that may facilitate an FDA reviewer’s use of the submitted data

• Helps the reviewer understand the relationship between the study report and the case report tabulation data

• The Study Data TCG does not define a specific template, but an example of a Study Data Reviewer’s Guide, including a template, completion guidelines and examples, can be found on the PhUSE website (https://www.phuse.eu/css‐deliverables).


(Study Data TCG, Section 2.2, 1st paragraph

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cSDRG Contents

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• The cSDRG (cSDRG.pdf) should include, but is not limited to the following: • Study protocol title, number, and version • Study design • Study overview• CRF data not submitted• Domains present and whether are standard, custom, efficacy, safety, or

have SUPP‐‐ datasets• Data conformance summary• Legacy Data Conversion Plan and Report (as appendix)


cSDRG Study Overview Examples

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• Are the submitted data taken from an ongoing study?• If yes, describe the data cut or database status.• Were the SDTM datasets used as sources for the analysis datasets? • If no, what were the sources of analysis datasets? • Do the submission datasets include screen failures?• If yes, which datasets include screen failure data?• Were any domains planned, but not submitted because no data were collected? • If yes, list domains not submitted.• Are the submitted data a subset of collected data?• If yes, describe the reason that all collected data were not provided.• Is adjudication data present?• If yes, describe the implementation approach and location of the adjudication data.


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Legacy Data Conversion PlanShould:• Describe the legacy data and the process intended for the conversion• Present the results of the conversions, issues encountered and resolved, and outstanding issues• Be included in the cSDRG



Study Data Reviewer’s Guide Resources (1)

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https://www.phusewiki.org/wiki/index.php?title=Study_Data_Reviewer%27s_Guide

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Study Data Reviewer’s Guide Resources (2)

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https://www.phuse.eu/css‐deliverables

Analysis Data Reviewer’s Guide (ADRG) (1) Provides the FDA reviewers with context for analysis datasets and terminology Purposefully duplicates limited information found in other submission documents in order to

provide FDA reviewers with a single point of orientation to the analysis datasets The Study Data TCG does not define a specific template for the Analysis Data Reviewer’s Guide,

but an example of an Analysis Data Reviewer’s Guide, including a template, completion guidelines and examples, can be found on the PhUSE website(https://www.phuse.eu/css‐deliverables).


Study Data TCG, Section 2.3

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Analysis Data Reviewer’s Guide (ADRG) (2)• Recommended as an important part of a standards‐compliant analysis data submission for clinical trials

• Provides FDA reviewers with context for analysis datasets and terminology• Provides a summary of ADaM conformance findings• Purposefully duplicates limited information found in other submission documents in order to provide FDA reviewers with a single point of orientation to the analysis datasets

• Specific template not provided, but an example, template, and completion guidelines can be found on the PhUSE website (https://www.phuse.eu/css‐deliverables).

Study Data TCG Section 2.3


• One per submission• Describes the submission of standardized study data.• Assists FDA in identifying potential data standardization issues early in the development

program. • Sponsors may also initiate discussions at the pre‐IND stage. • Prepare and include as part of IND.• Update / submit as additional studies are planned.

Study Data Standardization Plan (1)

Study Data TCG, Section 2.1


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The Standardization Plan should include, but is not limited to the following: 1. List of the planned studies 2. Type of studies3. Study designs (e.g., parallel, cross‐over)4. Planned data standards, formats, and terminologies and their versions, or a

justification of studies that may not conform to the currently supported standards


Study Data Standardization Plan (2)

Study Data Standardization PlanPhUSE Resources

https://www.phusewiki.org/wiki/index.php?title=Study_Data_Standardization_Plan_(SDSP)

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• Sponsors should provide the software programs used to create all ADaM datasets, and to generate tables and figures associated with primary and secondary efficacy analyses.

• The specific software utilized should be specified in the ADRG.• Software programs should include sufficient documentation to allow the reviewer to understand the submitted programs.

• Software programs should be provided as ASCII text files.



Software Programs






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Traceability• Traceability can be enhanced when studies are prospectively designed to collect data using a standardized CRF, e.g., CDASH.

• Traceability can be further enhanced when a flow diagram is submitted showing how data move from collection through preparation and submission to the Agency.



Traceability and Legacy Data Conversion• Sponsors should use processes for legacy data conversion that account for traceability. • To mitigate traceability issues, FDA recommends:

• Prepare and submit a Legacy Data Conversion Plan & Report.• Incorporate the Legacy Data Conversion Plan & Report into the cSDRG in order to record significant data issues, clarification and explanations of traceability.

• In some cases legacy data may also need to be submitted.• Sponsors should provide two separate CRF annotations:

• Based on the original legacy data• Based on the converted SDTM data.

• It may be helpful to provide mapping specifications from legacy to SDTM data (not in Study Data TCG).



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Study Start (1)• Ideally, create database based on the STDM.• Ideally, create CRFs based on CDASH and using CDASH/SDTM Terminology.• Create define.xml file(s) for datasets to be submitted. • Create the aCRF.• Develop protocol with the goal of being consistent with CDISC Controlled Terminology.


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Study Start (2)• If using legacy database, create all mapping specifications to SDTM domains, variables, and terminology.

• Develop SDTM‐compliant data‐transfer specifications for data from external vendors (e.g., Labs, ECGs, PK). If not, create mapping specs.

• Create SDTM/SDTMIG Trial Design Domains– This information should be able to be obtained from the protocol and/or CRFs– Doing this at the beginning can help eliminate inconsistencies with the protocol and CRFs







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Preparing for Submission: Data Packages


Component Tabulation Analysis Legacy DataDatasets Based on the SDTMIG, SENDIG Based on the ADaMIG Sponsor formatDefine.xml √ √ √aCRF Mappings to SDTMIG/CDASH N/A Annotated to legacy

datasetsReviewer’s Guide cSDRG, nSDRG ADRG cSDRG, nSDRGSDSP One for a submission N/ASoftware Programs Possible if LDC √ Not mentioned in TCG,

but folder exists in eCTD

CRO

Vendor

SponsorInternal Data

EDC

SubmissionData

Preparing for Submission:Identify Data Sources and Paths


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Preparing for Submission:Make Decisions

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What standard(s) will be used? Will there be an internal standard to which CROs/vendors will be held? Will there be legacy‐data conversion?


Preparing for Submission:Determine Responsibilities

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Who will manage the standard(s)? If there are multiple partners for conversion or creation of

SDTM datasets, who will: Ensure consistency of data? Manage resolution of differences?

Who will ensure datasets are compliant? Via validation tools Via human review

Who will prepare other necessary documentation? cSDRG SDSP define.xml


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Learning Objectives Reviewed

• Understand the regulatory basis for the requirement for electronic data and standardized electronic study data

• Become aware of the specific data standards the agency expects• Recognize that additional documents/files are required to support the submission of study data


FDA Study Data Standards Resources

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http://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm

1. FDA Data Standards Resources• FDA Data Standards Catalog v6.1 September 9, 2019• Study Data for Submission to CDER and CBER• Data Standards and Terminology Standards for Information Submitted to CDRH• Study Data for Submission to CDER and CBER

2. FDA Guidance Documents• Electronic Submissions Guidance List• Providing Regulatory Submissions in Electronic Format - Standardized Study Data:

Guidance for Industry (Dec. 2014)• Providing Regulatory Submissions in Electronic Format - Submissions Under

Section 745A(a) of the FD&C Act: Guidance for Industry (Dec. 2014)• Providing Regulatory Submissions in Electronic Format - Certain Human

Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications: Guidance for Industry(May 17, 2015)

3. Technical Guides• Study Data Technical Conformance Guide v. 4.3, March 2019• Technical Rejection Criteria for Study Data

4. Standardization Plan Recommendations• CDER/CBER Study Data Standardization Plan Recommendations


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Fred WoodVice President, Consulting ServicesSDTM and SEND Implementation [email protected]

Data Standards Consulting Group, A Division of TalentMineProviding Expert Consulting and Training on:• SDTM• ADaM• CDASH• SEND


Contact Information

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