25-Apr-2014 FDA/DCDISC Workshop. ›Introductions ›Housekeeping Rules ›Thanks –Colleen Ratliffe ›What is DCDISC? Welcome.

25-Apr-2014

FDA/DCDISC Workshop

› Introductions

› Housekeeping Rules

› Thanks– Colleen Ratliffe

› What is DCDISC?

Welcome

› 9:00-9:15 – Gathering & Welcome

› 9:15-9:30 - FDA/CDER State of Data Standards – Mary Ann Slack, Ron Fitzmartin - CDER

› 9:30-9:45 - FDA/CBER State of Data Standards – Lise Stevens, CBER

› 9:45-10:45 –Challenges with Incoming Data – Doug Warfield, Lisa Lin – CDER, eData Team

› 10:45-11:00 – Break

› 11:00-11:40 – “The Importance of CDASH – A Statistical Reviewer’s Perspective” – Ben Vali, CDER

› 11:40-12:15 –Challenges with Submission Data – DCDISC Team

› 12:15-1:00 – Lunch/Networking

Agenda

Ingeborg HoltJane DiefenbachAlan Meier

Challenges with Submission Data

Ingeborg HoltBooz Allen Hamilton

Technology Provider Perspective

› The ideal conditions for this are:1. The problem is clearly defined 2. The input sources are known and have stable

formats3. The desired functionality and output are

distinctly described

Technology Provider’s Task: Apply Knowledge in Order to Solve a Problem

• Problem: High incidence of spilt milk

• Input: Milk • Functionality: (1) Allow

drinking of milk from the cup (2) Minimize spilling when the cup isn’t oriented properly

1. The problem: Can it be determined from the submission data if the drug under review is safe and effective?

2. The input: Submission Data

3. The functionality: The analyses that need to be performed to determine the quality and completeness of the data and the safety and efficacy of the drug.

Technology Provider’s Task and Submission Data

› Data standards (CDISC SDTM and ADaM) – Organize submission data in a systematic way– Control terminology – Reduce the work needed to locate and understand

the data and create functionality– Increase the potential to reuse functionality

The Role of Data Standards is to Regulate the Input

› Success using data standards has expanded the scope of the problem to be solved

The Problem Definition has Changed

Is this drug safe and

effective?

How can the question “Is

this drug safe and effective”

be answered in the more

efficiently and effectively?

How can data collected for

answering the question “Is this drug

safe and effective” be reused to inform

drug safety and public health in

other ways?

How can submission data be

better modeled for its intended use, effective

reuse in drug safety and public health AND

assist drug development the pre-

competitive space?

scope

time

› Data standards change and grow as the problem changes and grows– Adherence to principles of the standard– Early communication

› Correct implementation of the standard– Requires

› Sponsors understand which standards are accepted› Data validation requirements are unambiguous

– Single Set of Validation Rules › OpenCDISC rules, FDA rules, rules from other organizations› Rules based on IG versus common sense rules

– Checks between standards (SDTM, ADaM)› The implementation guides are as specific as possible and cover

expected scenarios– Pharma SUG 2012 paper (Octagon)

› EX domain often implemented incorrectly› Time and practice: implementation is improving

Challenges to Standardized Submission Data

› Analyses for safety are well defined– Therapeutic area domains may require special analyses for

safety

› Efficacy analyses, particularly those using therapeutic area domains, may be complex and present new challenges

› Guidance needed for derived variables– How much support should be provided for missing values

that can be derived (eg imputing BLFL, STDY)– Should derived SDTM variables be validated?

Well Defined Functionality and Output

• Adherence of submission to data standards is improving

• Many of the new challenges result from an expanded problem space

• There are areas that need attention and work

Technology Provider Perspective on Submission Data

› Good Technology Choices– Designing tools to handle expected change

› Terminology changes, variable additions/deletions, validation rule additions/changes

› Anticipating therapeutic area domains, interoperability needs

– What is the role of the Pre-competitive Community (FDA, CDISC and other Standard Development Organizations, Third Party Data Providers, Technology Providers, Sponsors,…) › Should information technology and data standards usage

decisions involve all stakeholders and open discussion about risk/benefit issues– Metadata Repository– Changes to Standards

Technology Provider’s Responsibility

Adventures in CDISC Consulting and eCTD Preparation

Jane Diefenbach, PharmaStat LLCDCDISC Implementation Network at FDA

April 25, 2014

Preparing for a data submission

• 18 to 24-month lead time• Legacy studies and Phase III may just be

starting• Everything is changing: people, processes,

knowledge of the product, often even the company structure

• When standards change too it can be hard to accommodate them in this environment

Google Images for eCTD Preparation

What needs to happen

• Planning– What studies? What data formats? What standards?

• Production – legacy studies– Align the studies with a unified modeling plan– Perform the conversions, verify with reanalysis

• Production – current studies– Real time conversion and linear data flow is difficult

• Documentation, maybe most important

Planning the Submission: Company XYZ Data Flow

ADaM

eCTD

SDTM

Studies:

CDMS

101, 102, 103

Analysis

CSR

Item 11

eCTD

201, 202

CDMS

Analysis

CSR

eCTD

SDTM

203

CDMS

ADaM

CSR

eCTD

SDTM

301

Integrated Data for ISS

104

CDMS

ADaM

CSR

eCTD

SDTM

CDMS

ADaM

CSR

eCTD

SDTM

ADaM

eCTD

ISE

Credit John Brega 2014

Experience to Date

• Work volume is astronomical, easy to underestimate

• Clarity of purpose is sometimes absent– Standards are overwhelming; sponsors don’t know

what is most important– We imagine perfection at kick off; eventually just

need to get done– Downstream changes to standards, modeling are

costly; sometimes we need to say Next time

What makes it easier?

• Use of CDASH in data collection• Predictability of new standards, fair warning• OpenCDISC – has done more to standardize

implementation than anything• Electronic distribution of linked standards

(SHARe) and a data standards warehouse• Widespread adoption

What makes it easier?

• Communication!– The more we know about how you interact with

the data the better we’ll do– Guesswork leads to busy work and busy work does

not advance Science or Health

Google Images for CDISC Consulting

Alan MeierMedImmune LLC

Sponsor Company

› Implementation/Acceptance of Standards by Agency– Set time period for accepting submissions in new

version› Allows sponsor time to decide when to upgrade

– Work with CDISC to implement changes rather than publishing guidance› Saves time searching through documents

– Set policy on use of provisional / sponsor-defined domains› Are sponsor-defined non-X_, Y_, Z_ domains acceptable› Will provisional domain templates be accepted

Sponsor Company

› ADaM vs Sponsor-Formatted Analysis Data Sets– Will agency be requiring ADaM

› Versioning of CDISC Standards– Some products take 10+ years to develop– Acceptance of submission data in multiple versions

Sponsor Company

› Can we get an FDA representative on the Steering Committee

DCDISC