Cathy Barrows, Ph.D.GlaxoSmithKlineCo-Leader of CDISC Pilot ProjectCDISC ADaM Team

An Update on the CDISC SDTM/ADaM Pilot Project

FDA/Industry Statistics Workshop - 29 September 2006

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http://www.cdisc.org/

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CDISC Pilot Project was to…

Demonstrate that data submitted to the FDA using the CDISC Standard will meet the needs and expectations of both medical and statistical FDA reviewers.

Produce a worked example implementation of the available CDISC standards.

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How?

By conducting a case study legacy data (real clinical trial data, warts

and all) CDISC SDTM domains and ADaM datasets and associated metadata

submission of case study package to FDA for mock review

And in the process, identify any issues to be resolved in SDTM and ADaM models

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FOCUS: the package not the process

Choices/decisions guided by timeline realities of a team of volunteers from

multiple companies quick, efficient, effective - not

necessarily the most preferred option are not making recommendations re

process!

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Pilot Submission Deliverables

Submission package Includes SDTM datasets, analysis datasets, all relevant

metadata, analysis results, abbreviated report Review package tied together using metadata in

DEFINE.XML

Summary report of the pilot submission project issues encountered, strengths and weaknesses incorporate what we learned from the FDA feedback

Both to be made available to the public on the CDISC website

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Criteria for success of the Pilot Project

FDA statistical and medical reviewers will evaluate the submitted datasets (SDTM and AdaM), metadata and documentation Usable with their tools? Reproducibility of analyses, derivations? Navigable? Contents – what and where are OK? etc.

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And the verdict? We DID produce an electronic submission that

met the reviewers’ needs

The overall tone of the reviewers’ feedback was very positive

noted easier learning curve

The FDA review was very thorough and they provided constructive criticism

Issues encountered both by team and in FDA feedback are already beginning to be addressed by CDISC teams

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Now to details…

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Who? 15 core team members from industry FDA involvement

Unprecedented level of involvement Provided co-leadership 18-20 employees involved 12 consistently in contact with team includes medical and statistical reviewers

Interactions: regular team teleconferences Feb. face-to-face meeting to define the project

(expectations/requirements) Pre-submission encounter Feedback from review

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FDA representatives - expectations, requirements, wish list

Key messages: Consistency, accuracy, completeness are

extremely important - follow the specifications!

Define file crucial, but needs to be accurate Clear mapping between the plans for

analysis, the tabulation data, the analysis data, and the analyses performed

SDTM and Analysis datasets should be available for both medical and statistical reviewers

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Presubmission “Encounter”

Important opportunity to communicate about those crucial data-type issues that we run out of time for at “usual” meetings

Discussed data to be submitted - structures, variables

FDA was able to make specific requests, for example: Hy’s Law analysis dataset (liver hepatotoxicity)

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Legacy data used in the pilot submission Real clinical trial data, provided by Eli Lilly Data de-identified, documents redacted

Indication: Alzheimer’s Randomized, double-blind, placebo-controlled,

parallel-group study Three treatment arms: low dose, high dose, placebo Approximately 300 patients, multiple centers

Representative set of endpoints and analyses included in package

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CDISCPILOT01

M1(Administrative)

M5(Clinical Study Reports)

Reviewer’s Guide PDF

Cover Letter PDF Study Report Datasets

Study Report PDF Analysis Tabulation

DEFINE XML

Analysis Datasets XPT

Annotated CRF PDF

DEFINE XML

SDTM Datasets XPT

CDISC Pilot Submission Package Content

• PDF TOCs and eCTD folder structure

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Legacy documents

received

Decisionsregarding data

analysis

Write SAPMap blank CRF

to SDTM(aCRF)

Create SDTMdata metadata

Create analysisdata metadata

Create SDTMdatasets (littlederived data)

Create analysisdatasets

Receive legacydata

Create 0-obsanalysis datasets

Coding ofevents data &con.med. data

Write studyreport

Create 0-obsSDTM datasets

FinalizeSDTM datasets

Generateanalyses

Derived datato SDTM

Create analysisresults metadata

Note that “create” includes QC steps.

Write reviewer’sguide

Write cover letter

Create DEFINE

Create XPT files

Building the CDISC Pilot Submission Package

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Presentation of the Define

FDA expectation: Pilot package in Define.xml

The Define file integrates tabulation dataset (SDTM) metadata analysis dataset (ADaM) metadata analysis results (ADaM) metadata

New implementation! Exciting!

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Illustration of the Pilot Submission Package

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Top of Define file

Table of ContentsIdeally would also have included

a link to reviewer’s guide

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Define file: List of Analysis Datasets

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Define file: Metadata for ADSL

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Define file: Code List

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Define file: Computation Method

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Define file: List of Tabulation Datasets

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Define file: List of Analysis Results

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Define file: Analysis Results Metadata

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Define file: Linked to Study Report

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Inclusion of Programs?• Elected to not include entire “program”• Included program code in metadata for repeated measures analysis• This WAS used in the review

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Next Steps:Wrap up tasks for this iteration

Some revisions to current package Implement some of the FDA feedback Fix a few things that are errors or oversights Incorporate some things we wish we had done

Complete the project report

Publish the package and the project report

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Future iterations might: Fully and completely work this example (rather than a subset) More fully develop the metadata Include datasets in the DEFINE file, instead of separately XPT

files Use studies from other therapeutic areas Go beyond a single study Test submitting different sets of sponsor data (e.g., NDA, safety

update) Address how to send updates (e.g. additional derived variables)

effectively Test newer versions of models, e.g.:

ADaM PK data Pre-clinical data ODM

Test other analysis strategies

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Our Advice -Wisdom is scar tissue in disguise

Or, as one FDA Review Team member said:

In order to get a standard we have to suffer

It’s worth

it!

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XML

and

You

SDTM

ADaM

ODM

CDISC

Pilot