PhUSE WS4 Subteam Meeting Minutes
March 18-19, 2013
Attendees: See last page for contact information
Co-leads: Susan Kenny, Gail Stoner, with Jingyee Kou, and Stephen Wilson as FDA co-leads.
Meeting Summary
We reviewed the nearly published Submission Data Review Guide (SDRG) and agreed that the Analysis
Data Review Guide (ADRG) should follow a similar format. We made the following high level assumptions:

All Reviewers will reference both the SDRG and the ADRG.

There is a linear flow of file creation process where ADaM domains are created from
SDTM.based domains yet we recognize the need to have a section of the ADRG describe any alternate process such as ADaM domains being created from non-SDTM domains.

We will develop a ADRG template for a single study rather than for an ISS/ISE in mind.

We do not want to repeat important information that is in the clinical study report (CSR) or the statistical analysis plan (SAP) in the ADRG. Instead important information would be called out but links provided to direct reviewer to more information.
Monday Afternoon March 18:
During the first day, we brain stormed about topics that should be discussed in the ADRG. The following categories of topics were discussed:

Analysis level information that relates to multiple ADaM domains such as visit windowing, imputation methods, core variables, differences between SDTM and ADaM variables (e.g. ARM vs. TRTxxP, population flags, baseline values)

Topics related to individual ADaM domains

Key information from the SAP that relates to content of ADaM domains (notably ADSL)

Study level issues such as data cutoff procedure, degree of mis-randomizations or dosing issues, screen failures, etc.)

Submission of programs

Sponsor variable naming conventions
Timelines and Meeting schedule
The following was presented as our target timelines:
Determine the scope of the ADRG (e.g. analysis datasets, programs, overlap with SDRG)
Complete during CSS
Develop draft ADRG template and completion instructions
Vet draft ADRG template and completion instructions
Finalize draft ADRG template and completion instructions and develop ADRG examples
Release ADRG work package for public comment
Finalize ADRG work package and release for use
2 months
1 month
3 months
1 month
1.5 months

We agreed to have meetings every other week. We have a number of EU representatives so we wish to have our meetings at an EU friendly time. This may end up being early for the very few west coast team members.
Tuesday afternoon, March 19
During the second day, we divided into two groups to discuss specific issues related to 1) Study level and analysis level information and 2) Information pertaining to individual ADaM domains. These ideas have not been discussed by the entire group and need to be organized into a coherent outline. However, the rough ideas are as follows.
Study Level and Analysis Level Information
Introduction

Same people or different people who use SDTM? Assume reviewers are reading both.
Protocol Design

Protocol for SDTM; SAP for ADaM – key information

Should we replicate SDRG content? Link to it?

Schema plus annotation of ADaM variable interpretation (APERIOD, APHASE, ASPER, etc) and relationship to TRTxxP

Graphical presentation may be easier than text

What other details would we include from SAP/protocol? o Duplication from Trial Summary domain?
Data Section

Overview of what data are included (e.g., screen failures dropped from SDTM)

Brief introduction to primary/key/important analysis and what types of datasets/analyses support them. Methods

Similar to analysis results table – reason for creation of each AD
Random idea list related to analysis level information

Windowing

Describing intermediate analysis datasets and final dataset

Data flow to ADaM – any circularity

Data dependency, order of creation

Data included – screen failures, cutoffs, etc

Missing data – imputation methods in general – link to values of DTYPE

Overlap/differences between SDTM and ADaM – pop flags, --BLFL, treatment emergent, ARM vs
TRTxxP; ACTARM vs TRTxxA o What is found in both places, how are they the same or different


Complicated derivations with diagrams

Pre-processing before applying derivation rules (e.g., collapsing records)

Core variables – vars copied onto other datasets; subject-level, visit/cycle-level

Data workarounds and rationale

Lookup tables (events [SMQ] or meds of interest); external data sources not in SDTM

“Mis-randomizations” – TRTxxP vs TRTxxA (and ARM vs ACTARM) o When to include subject IDs?

Scoring algorithm? Keep it here vs in SAP vs CSR

When are TRTxxP used vs TRTxxA; also how are pop flags used in analysis

Answer any obvious questions o Why is there limited data for a domain o How subjects who switched sites were treated for analysis

Might have questions such as “Were there any cases of xxx?” Impact on analysis.

General caution about presenting info that overlaps with CSR; might reference CSR instead

Overview/index of programs submitted

Discussion of programs and whether they are executable

Compliance issues
Dataset Level Information
Overview/Intro

What is in here? o All ADs used for analysis vs subset (describe) o Programs creating ADs o Analysis results metadata o Programs to generate analysis results

Data flow, dependencies o Flow chart might be helpful. Start with SDTM to final AD. Very useful when you have composite EP or highly summarized datasets. o Keep it pretty high level. Not intending to get into detail of which SDTM fed into which
ADaM. o Should absolutely not go more than one page.

Data cutoff, screen failures included, etc

General/common info re ADs

Split files – what was split, basis for split [This might go below]

What ADSL variables were copied to other datasets [Might also go in ADSL section]; key patientlevel info

Sponsor variable naming conventions

Dataset TOC
Order:

Same order as define (current preference of this group)

Alpha

Some sort of grouping
Columns


We’ll provide a default set, but sponsor may add or subtract
E.g., might want to do a further breakdown for AEs of special interest, Hy’s Law, etc
Other considerations:

How to show split datasets
DSN
Origin of datasets
Intermediate vs used for analysis vs both
Exploratory
BDS vs TTE, etc
Might prefer a flowchart
Safety
Primary EP
Secondary EP
Efficacy
PK/PD
Other
Dataset Detail
DSN description:
This dataset contains …
How you pulled data from multiple sources eg for a composite endpoint
ADSL: These are the variables that we used for stratification or subgroup analysis
Explain any differences with corresponding or related SDTM variables
ADAE: description of variables to support specific events of interest valuable

Caution: Avoid duplication/overlap with SAP content or detailed algorithms in define. Important to ensure consistent definition.
This is a reference data… Briefly describe its content and intended use. Also note where it is (e.g., with programs? With data?)
Detailed definition/algorithm that does not work well in define.
Role of important vars – primary EP, sensitivity, exploratory
Parameter guide to ensure understanding of how to use data
What is relationship between SDTM and AD record count? Were SDTM data excluded and why?
Try guided question approach:

Are there any datasets that differ from SDTM?

AE: were any std queries used? If yes, provide details

ADSL: what grouping and selection variables, any relevant details

Any issues with study conduct that impacted AD?

First
Gail
Susan
Last
Stoner
Kenny
Organization
J&J
Amgen
Michael Frederiksen Novo Nordisk
Sarah Cannon Research
Albert Chau Institute
Nancy
Cathy
Beate
Lex
Friedland
Bezek
Hientzsch
Jansen
IBM
Astellas Pharma
Accovion
SAS
Lou olivier
Yimei
Florio leconte
Wang
Victor Falch
Megumi Fujimoto
Chris Price
Yuguan Zhao
Misty
Adam
Sudhir Singh
Steven Light
Steve
Linda
John
Mina
Odle
Huang
Wilson
Collins
Brega
Hohlen email gstoner@its.jnj.com
susan.kenny@amgen.com
minf@novonordisk.com
albert.chau@scresearch.net
nefried@aol.com
cathy.bezek@astellas.com
beate.hientzsch@accovion.com
lex.jansen@sas.com
Phone
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Boehringer Ingelheim yimei19@yahoo.com
Theorem Clinical
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Eisai
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Lilly
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