It Should be Simple Right?files.massbio.org/file/BSDMCT01182018.pdfOur Experience with CDASH •We rolled out our first standard (e)CRFs in 2009 •When CDASH 1.0 was released in 2008,

Standards Implementation:It Should be Simple Right?

Thursday January 18, 2018

Upcoming MassBio Forums

January 18, 2018; 4-6pm: TODAY!!

2018 JP Morgan Recap: An Insiders View BD/Fin & EU

February 1, 2018; 8-10am:

NASH: A Silent Epidemic Poised to Swamp the BioPharma

Industry? DD

February 28, 2018; 9-11am:

RARE DISEASE DAY FORUM: Shortening the Diagnostic

Journey for Children with Rare Diseases L&R

Who is in our audience today?

In a show of hands …

What are we talking about?Definitions of Standard

Something considered by an authority or by general consent as a basis of comparison; an approved model

An object that is regarded as the usual or most common size orform of its kind

An average or normal requirement, quality, quantity, level, grade,etc.

What are we talking about?

Clinical Data Interchange Standards Consortium (CDISC) develops data standards, such as SDTM, ADaM, and CDASH, that enable information system interoperability to improve medical research and related areas of healthcare”

SDTM – Study Data Tabulation Model: The content and tabulation standard for regulatory submission of case report form data tabulations in clinical research studies.

CDASH - Clinical Data Acquisition Standards Harmonization

Pinnacle21 report - Software, Pinnacle 21 Enterprise (used at FDA under the name “DataFit”), which provides biopharmaceuticals a means to test if their submission data is compliant (formerly known as OpenCDISC)

Domain- a collection of observations (data) with a common topic

Define.xml – a document that describes the structure and contents of the data collected during the clinical trial process

Controlled terminology - the set of CDISC-developed or CDISC-adopted standard expressions (values) used with data items within CDISC-defined datasets

ADaM - Analysis Data Model: The content standard for regulatory submission of analysis datasets and associated files

Why would we do it What are the Pros of using standards?

Company

Reduce resource

Increase Morale

Messaging/reporting simpler

Department

Consistency beyond just CRFs / SDTMs

Flexibility of assigning resources (Anyone can

work on anything)

Easier to Validate-using standard tools

External to company

Consistency is presented to external

partners

External Partners can build Efficiency into

their process

Do we have to do it???

Similar to wearing a seat belt in Massachusetts-It is a good practice to do – but it is also the law

Agenda

• How to Implement Standards

• What is the CRO perspective to implementation

• What is the Sponsor perspective

• What is needed for a submission

– Legacy studies versus standard submissions

• Where will the standards be going next

Standards Implementation:It Should be Simple Right?

Speakers:

• Susan Boquist, Associate Director, Statistical

Programming, PROMETRIKA, LLC

• Wendy Mangels, Associate Director, Clinical Data

Management, Vertex Pharmaceuticals.

• Brian Conley, Associate Director, Statistical Programming

and Data Management, Clementia Pharmaceuticals Inc.

Moderator:

• Michelle Harrison, Associate Director, Clinical Data

Management at Vertex Pharmaceuticals.

©2017 Vertex Pharmaceuticals Incorporated

Making Standard (e)CRFs Work

Wendy Mangels | 18JAN2018

Who

11 ©2017 Vertex Pharmaceuticals Incorporated

Clinical Data Standards Committee

• Develops and reviews standard

(e)CRFs, edit checks, CRF

Completion Guidelines, external data

transfer specs

• Approves/rejects requests for non-

adherence to standards

Steering Committee

• Approves standards for use

• Sets expectations that dept follows

standards

• Adjudicates requests for non-

adherence which Standards Committee

cannot resolve

Biostatistics Department heads from functions on

Standards CommitteeClinical Operations

Clinical Pharmacology

Data Management

Global Patient Safety

Medical Directors

Medical Writing

Statistical Programming

Liaisons from Biomarkers and Regulatory,

as needed

What

• Our standard (e)CRF is a Word document right now

– applies to paper or electronic CRFs

– platform-independent

– room for instructions


Our Experience with CDASH

• We rolled out our first standard (e)CRFs in 2009

• When CDASH 1.0 was released in 2008, we didn’t feel it had

the same level of maturity as a standard as SDTM or ADaM

did

– Question phrasing can be clunky (“Indicate if ECG was performed”)

– In many cases, SDTM presents multiple options, but CDASH has

“one right way”

– Nowhere to put some of the data we collect

• There seems to be a lag between SDTM releases and relevant

CDASH standards

• Our chosen path involves SDTM-like data collection, rather

than CDASH


CDISC SDTM Compliance

We maintain “CDISC-friendly” standards

– Dataset names are SDTM domain names (AE, DM, etc.)

– SDTM variable names (whenever practical - e.g., flat forms)

– SDTM Terminology (whenever practical)

– We don’t use a normalized Vital Signs structure in the eCRF, but

we make it easy to transpose the data. The variable names

(HEIGHT, TEMP, etc.) are the SDTM Vital Signs Test Code

(VSTESTCD)


Compliance

Encouragement

• Opportunity for input (at our company and at partners)

• Training

• Flexibility - standards need to work in actual studies (multiple study

drugs, pediatric trials, oncology, …)

– FAQ document with pre-approved changes

– Electronic system for requesting non-adherence, or new/modified

standards

– Multiple versions of appropriate (e)CRFs

Enforcement

• Department heads approve standards

• Independent QC Checks of all (e)CRFs to ensure standards used

correctly


Encouraging Compliance: Color-coded FAQs

16

Preapproved

Change

Changes NOT

Preapproved –

Needs CDSC

Review

Changes Not

Recommended

Commonly

requested pre-

approved changes

Save time – these

requests are

unlikely to be

approved

Submit a CDSC

request

Encouraging Compliance

FAQ document with pre-approved changes


Encouraging Compliance

Electronic system to request non-adherence or modifications

(SharePoint list with workflows)


Study XYZ-001

Hera Xiao

Innovative Clinical Development Solutions

Implementation Successes and

Challenges from a CRO Perspective

Susan Boquist

MassBio

January 18, 2018

21

▪ Misconceptions on the meaning of “Standard”

▪ Sponsors have different flavors of “SDTM”

▪ Sponsors that are overly involved or absent

▪ No control on source or content of raw data

▪ Late notice of concurrent mapping by other groups

▪ Scope creep

CRO Implementation Challenges

22

▪ Clear understanding of the path forward

▪ External eDC built predictably

▪ Efficiencies of code for known data mapping

▪ Downstream efficiencies in analysis

▪ Resourcing flexibility

▪ Cost savings

CRO Implementation Successes

CONFIDENTIAL

CONFIDENTIAL

SDTM Challenges From Sponsor PerspectiveBrian ConleyJanuary 18, 2018

23

CONFIDENTIAL

Sponsor’s Perspective

▪ Communication is important

▪ Sponsors need to participate in implementing their standards

▪ Encourage CDISC interest in sponsor organization

CONFIDENTIAL

Communication – Lessons Learned

▪ Incorrect (old) version of Pinnacle21 is run– Vendor “set” the validation version at the beginning of the study and does

not want to fix newly uncovered issues which may have been hidden in an old Pinnacle21 version

▪ After many rounds of updates, Issue Log becomes hard to follow– Agree on a naming convention, prefer to use date in filename– Use the same format

• Does CRO respond adding columns to the right, or start new rows below the issue?

– Do not only send issues as emails• Sometimes emailing screenshots along with the spreadsheet helps

▪aCRF planned to be completed at the end of the study. – Our preference is for creating the aCRF before beginning the SDTM

programming

CONFIDENTIAL

Sponsor Participation at Study Startup

▪ SDTM Implementation should begin with database development

– Sponsors are typically closer to database development than SDTM group at vendor

• SDTM team may be at a different CRO than the Data Managers

– CRF review is critical time to align with CDISC standards

• Every field on the CRF should have a home in SDTM

• Controlled Terminology will come back to haunt you

– Have internal discussions on whether to be consistent with earlier studies, or “fix” things in new study

• Hospitalization events were in custom domain in previous studies, use HO for new study?

• AEOUT terms do not follow Controlled Terminology

26

CONFIDENTIAL

Sponsor Participation at Study Startup

– Provide CRO with as much of the mapping details as possible

• --TEST/--TESTCDs used in previous studies

• Custom domains

• Lab Conversion factors

• Therapeutic Area User Guide (TAUG) references

• aCRF?

27

CONFIDENTIAL

Encourage CDISC Interest

▪When CRO delivers SDTM data to the Sponsor, who reviews?

– At smaller sponsor companies, might be only one person

▪ How can we expand CDISC knowledge at our company?

– Keep an eye out for PhUSE Single Day Events (in Boston April 26th, 2018!), local PharmaSUG, Boston Area SAS Users Group (BASUG), MassBIO meetings

– Become a CDISC Member

• In the Member’s Only area of CDISC.org:

28

CONFIDENTIAL

CONFIDENTIAL

Legacy Data Submission

CONFIDENTIAL

FDA Study Data Technical Conformance Guide

▪ https://www.fda.gov/downloads/forindustry/datastandards/studydatastandards/ucm384744.pdf

▪ 8.3.2.2 Legacy Data Conversion Plan and Report▪ Sponsors should evaluate the decision involved in converting previously collected nonstandardized data

(i.e., legacy study data) to standardized data (i.e., SDTM, and ADaM). Sponsors should provide the explanation and rationale for the study data conversion in the RG. To mitigate traceability issues when converting legacy data, FDA recommends the following procedures:

– 1. Prepare and Submit a Legacy Data Conversion Plan and Report.

– 2. Provide an aCRF, for clinical data, that maps the legacy data elements.

– 3. Record significant data issues, clarifications, explanations of traceability, and adjudications in the RG.

– 4. Legacy data (i.e., legacy aCRF, legacy tabulation data, and legacy analysis data) may be needed in addition to the converted data.

https://www.fda.gov/downloads/forindustry/datastandards/studydatastandards/ucm384744.pdf

CONFIDENTIAL

Is Legacy Data “Submittable”

▪ Legacy data should be submitted as SAS V5 Transport files

– Specifications are specified in the “Study Data Specifications” document on the FDA websitehttps://www.fda.gov/downloads/ForIndustry/DataStandards/StudyDataStandards/UCM312964.pdf

▪ “For an individual study, all dataset names and dataset labels should be unique across both the analysis and tabulation datasets submitted for an individual study. The internal name for an analysis dataset should be the same as the name shown in the data definition file.”

CONFIDENTIAL

Is Legacy Data “Submittable” (Continued)

▪ Variable names may need to be resized:

▪ “The key variables (e.g., subject identifier and visit for datasets with multiple records per subject) should appear first in the datasets. Each subject should be identified by a single, unique subject identifier within an entire application (including tabulation, listing and analysis datasets). Subjects enrolled in a primary study and then followed into an extension study should retain their unique identifier from the primary study. “

Element Maximum Length in Characters

Variable Name 8

Variable Descriptive Label 40

Dataset Label 40

CONFIDENTIAL

aCRF for Legacy Data

▪ FDA requests that sponsors provide two versions of the annotated CRF

– One based on Legacy Data

– One based on SDTM Data

▪ The Legacy CRF should include all versions and all forms

CONFIDENTIAL

Define.pdf for Legacy Data

▪ See Section 3.1.2.2 in “Study Data Specifications” document

– “For datasets not prepared using CDISC specifications, sponsors should include a define.pdf to describe the datasets for each study…”

– Also provide definitions of each variable

– First page should list a table of all datasets, with description and location

– There should be a hyperlink from this first page to the dataset within the define.pdf

– Also hyperlink to the SAS XPT file

Future of CDISC

Susan Boquist

MassBio

January 18, 2018

36

▪ Make documentation easier to use

▪ Make it easier to volunteer

▪ Resolve the inconsistencies

▪ When is the next version getting published?

▪ What are you working on?

▪ HELP!

What CDISC Members are Saying

37

▪ More support for volunteers

▪ Improved standards development process

▪ Accredited training program

What CDISC is Doing

38

▪ Consistent onboarding and training

▪ Set clear expectations

▪ Hours tracking and succession planning

▪ CDISC Staff support for foundational teams

More Support for Volunteers

39

▪ Global Governance Group (GGG) implementation

▪ Wiki collaboration space: wiki.cdisc.org

• CRF Maker

• SDS Maker

▪ Jira issue tracking: JIRA.cdisc.org

Improved Standards Development

Procedure

40

▪ CDISC Education recently received accreditation from

the International Association of Continuing Education

and Training (IACET)

• Independent assessment and confirmation of a high

quality, well controlled training program

Accredited Training

41

▪ Predictable release schedule

▪ New publishing formats

▪ Transparency and Predictability

▪ Future CDISC Standards

What’s Coming

42

▪ Early notice of expected product releases each year

▪ Quarterly Controlled Terminology (CT) releases

▪ Ad hoc TA User Guide releases with Provisional status

▪ Annual Foundational Standards release (first week of

November)

• For standards with finalized components by cut-off date

• Provisional standards with all content finalized by cut-off

date also gain Final status

Predictable Release Schedule (1)

43

Final now means:

▪ Public review completed on:

• Normative standard

• Informative examples & text

• Conformance Rules

• Controlled terminology

▪ Publication-ready updates made

▪ Metadata in CDISC SHARE

▪ Education components developed

Predictable Release Schedule (2)

44

▪ Piloted the release of their first HTML standard

• CDASHIG v2.0

• CDASH Model v1.0

▪ Benefits

• Much shorter publication time

• More universally readable than PDF

• But…you can export a PDF if you want one, or save the

HTML file for offline use

New Publishing Formats

45

▪ Pipeline

• Volunteer View – Wiki

• Public View – Website

• List of Draft Domains - Website

Transparency and Predictability

46

▪ Refine the standards to build more support for new

technologies

• Connect CDASH (and SDTM) with FHIR and other

healthcare standards to support eSource

• Align SDTM Pharmacogenomics with global genomics

initiatives (GA4GH, HL7 Clinical Genomics, ISA-Tab &

Workflow initiatives)

• Provide standards in new formats (RDF)

• Support machine readable standards

• Single instance of each concept, well defined

• Build biomedical concept templates

Future of CDISC Standards (1)

47

▪ Expand use cases beyond regulatory submissions

▪ Align models with Real World Data (RWD)

Future of CDISC Standards (2)

48

▪ Alignment and consistency within and across models

▪ Clearly defined concepts to reduce ambiguity and

help identify gaps

▪ Documented principles will guide future development

▪ Higher quality standards

CDISC has been building the plane while flying it and

now they need help landing it

Expected Results

Thank you!

Upcoming MassBio Forums

January 18, 2018; 4-6pm: TODAY!!

2018 JP Morgan Recap: An Insiders View BD/Fin & EU

February 1, 2018; 8-10am:

NASH: A Silent Epidemic Poised to Swamp the BioPharma

Industry? DD

February 28, 2018; 9-11am:

RARE DISEASE DAY FORUM: Shortening the Diagnostic

Journey for Children with Rare Diseases L&R

Documents

It Should be Simple Right?files.massbio.org/file/BSDMCT01182018.pdfOur Experience with CDASH •We rolled out our first standard (e)CRFs in 2009 •When CDASH 1.0 was released in 2008,