1. Midwest User Network Richard Lewis Octagon Research Solutions

2. Agenda 9:00-9:20 Group Update 9:20-9:30 Portal Update
9:30-10:30 Discussion Questions
10:30-11:00 When to Integrate SDTM
11:00-12:00 Changes from to 3.1.2

3. To existing members and (many) new members
Welcome!
To existing members and (many) new members

4. Next Meeting Presentations
Vote on external presentations for next meeting.
define.xml team
ADaM team
ISD Pilot team
Controlled Terminology
Others?
Internal Presentation Volunteers
Implementing ADaM
Overcoming pitfalls

5. Lunch Meetings Successfully Used by Other User Groups Timing
Once a month
Topic Out Ahead of Time
Casual
Discussion rather than presentation
Interest outside the N IL area?
List of possible restaurants

6. CDISC Interchange
October 28th – 30th
Arlington VA

7. Portal Update

8. Portal Update

9. Portal Update Now ‘Midwest (Chicago)’ Adding Final Touches
Up and Fully Running Soon
With the caveat that we have been saying that since 2006

10. Portal Questions?

11. Discussion Questions (Cathy)
How are companies handling the release of new controlled terminology packages?
Should the database match what is on the crf, or is it ok to map values that are equivalent?
Are companies using the new LBTESTCD’s – example do you use “GLUC” for both serum glucose and urine glucose?  
Will we need to have separate testcds -  GLUC and UGLUC in ADaM, based on the recent draft ADAMIG?   

12. Discussion Questions
Are companies using RELREC for PC and PP, and/or other domains?  How does it get created?

13. Discussion Questions
Are companies including Screen Failure data in SDTM (DM, DS, SC)?

14. Discussion Questions
What methods are being used to control the quality of SDTM besides WebSDM?
WebSDM checks (Sandy VanPelt Nguyen)
Is the FDA using V1.5 or V2.6?
CDISC Website points to V1.5

15. Discussion Questions
What are companies doing for legacy conversions?  Do they create:
study SDTM
study ADaM
integrated SDTM
integrated ADaM

16. Discussion Questions
For integrated ADaM, are only data sets for SCE/SCS needed? Most likely, yes? For example, there is no need to have ADIE, ADPE…

17. Discussion Questions
Are SDTM aCRF’s needed for all studies, including those with screen shots only (i.e. EDC studies)? Usually, there are too many pages.

18. Discussion Questions
For submissions with CDISC data sets, do we still prepare patient profiles? (According to CDISC documents, it will not be needed.)

19. Discussion Questions (Susan)
When reviewing the ADaM model I was wondering how one documents the Source/Computational Method in the define.xml when
1) the *true* source of the collected data is an internal analysis dataset  (not SDTM)
2) the *true* source of the derived variable/parameter is an internal analysis dataset (not SDTM).
Should the ADaM define.xml describe the data in terms of the SDTM, even if the SDTM isn't the source of the data?  
What does one do if they produce SDTM and ADaM from their internal analysis datasets?  
Do you define ADaM in terms of SDTM to maintain transparency between ADaM and SDTM?  
Do you need to provide the computational method in the define.xml if the variable/parameter comes from another dataset?

20. Discussion Questions
For reference here are some excerpts from the ADaM Document: 1.1 Purpose The Analysis Data Model describes key principles that apply to all analysis datasets, with the overall principle being that the design of analysis datasets and associated metadata facilitate explicit communication of the content, input, and purpose of submitted analysis datasets Definitions Input Data – The data used for the creation of analysis data sets. Traceability – The property that permits the user of an analysis dataset to understand the relationship of analysis values to the study tabulation datasets Introduction Analysis datasets should facilitate clear and unambiguous communication of the content of the datasets supporting the statistical analysis performed in a clinical study, should provide a level of traceability to allow an understanding of the relationship of analysis values to the input data, and ...

21. From John
In many respects, ADaM is still about philosophy and the idea that analysis dataset metadata should refer to the input data is logical.
From the point of view of the recipient of the SDTM and ADaM data, it makes sense that ADaM refers to the study data tabulation in hand, rather than to input data that are not sent.  Otherwise, I think it would be difficult for a recipient of ADaM to verify the derivation of the datasets or to perform sensitivity analyses.
ADaM is a CDISC standard, and as such, I believe that ADaM metadata is about how you can get to ADaM from SDTM.  That wasn't always recognized so clearly as now.  This is partly the reason that there are some discrepancies perhaps between the documents/sections still.
ADaM may be in fact generated from a different source than SDTM, however if so, I think the metadata should still refer to SDTM as if it had been the source; and this is difficult if SDTM is not really the source.
CDISC now has a vision that CDISC metadata should be bidirectional and permit one to go from collected values through to analysis, and vice-versa.  Implicit or explicit in this is that ADaM metadata refer to SDTM.  The vision is CDASH-SDTM-ADaM-analysis (via ADaM results metadata).
Another thing, besides data, some have said that "input" may also refer to SAP, Protocol, third party algorithms, thresholds, etc.

22. From Susan
As you are probably aware, this has been a central issue for many ADaM discussions.  It is probably worth noting that in earlier versions of the ADaM standards, we did have SDTM as our ‘input’ box but some team members felt this was too restrictive and the oft cited adage that “CDISC can not endorse any particular process” was used to change the documentation to make it more generic.  In addition, even in the Linear process (SDTM first, then ADaM), because of timing, there might be inputs to ADaM that are not yet in SDTM (PK spreadsheets come to mind, randomization schedules, protocol deviations, etc.). 
But we tried to reinforce the concepts in words that there must be some describable relationship between SDTM and ADaM, regardless of what the input to ADaM is.  The way we approach this in the ADaM training is to emphasize that the FDA reviewer receives 1) the SDTM tabulation data and 2) ADaM data.  They do not receive any ‘raw’ data.  If their task is to understand what you did in the analysis, then it follows that they must understand this with the data they have in hand.  If they have questions about how you created a derived observation in ADaM, they are going to be asking this relative to the observations in SDTM.  You will be hard pressed to answer their questions if you do not understand the relationship between SDTM and ADaM.
Creating ADaM from something other than SDTM is not impossible and in fact there are more than a couple of large pharma’s who are doing it this way.  But it does add another layer of effort to create the trace between SDTM and ADaM. 

23. Discussion: When to Integrate SDTM (Yen)
Late Stage Conversions
Data collected in ‘legacy’ format
SDTM created in final stages
Analysis datasets created independently of SDTM
CSR may be written

24. Discussion: When to Integrate SDTM (cont)
Mid Stage Conversions
Data collected in ‘legacy’ format
Converted to SDTM after collection
Analysis datasets created from SDTM
Upstream
Data collected in SDTM (like) format
No or minimal conversion necessary

25. When to Integrate SDTM? Pros & Cons at each stage Late-stage:
Pro: Minimum disruption of business process
Pro: Fastest way to submit SDTM
Con: Submitted data not source for analysis
Con: Convert at time-critical point in project

26. When to Integrate SDTM? Mid-stage:
Pro: Midrange disruption of business process
Pro: SDTM data is source for analysis
Pro: Efficient data exchange w vendors & partners
Con: Convert at time-critical point in project

27. When to Integrate SDTM? Upstream, in collection systems:
Pro: Build SDTM, not convert to SDTM
Pro: Most efficient data exchange w vendors & partners
Con: Maximum disruption of business process

28. Changes
from
SDTMIG
3.1.1 to 3.1.2

29. Scope of Review Not domain by domain review
Review of changes in Section 4
Changes each impact many domains
Basic SDTM knowledge independent of SDTM domains
Although I couldn’t resist adding a couple of domains which had major changes at the end

30. 4.1.1.4 Order of the Variables Variable order no longer flexible
1) Identifiers
2) Topic
3) Qualifiers
4) Timing
Within each role order should be the order shown in 2.2.12.2.5 of the SDTM

31. 4.1.1.6 Additional Guidance on Dataset Naming
Custom domains beginning with X, Y or Z are reserved
Will not be used by SDTM in the future
Second letter can be any letter or number
Using X-, Y- or Z- is optional and not required

32. 4.1.1.7 Splitting Domains Why sponsors will split is not addressed
Two methods
General observation classes
Split by –CAT, which must be populated in all cases
FA Domain
Split by –CAT
Split relative to parent domain of the value in –OBJ
For example, FACM would store Findings About CM records.

33. 4.1.1.7 Splitting Domains (cont)
Other rules:
1) Values in DOMAIN remain the same
2) Domain prefixes use value in DOMAIN
3) --SEQ unique within USUBJID across domains
4) Variables with same name must have same length across datasets
5) Permissible variables do not have to be in all of the datasets

34. 4.1.1.7 Splitting Domains (cont)
Other Rules: (cont)
6) Up to 4 character dataset names
First two letters are the same as the original domain
7) SUPPQUALs of split domains also split
SUPPQS36, SUPPFACM
8) RELREC relationship defined for split FA domains may reference 4 character dataset name

35. Splitting Domains - Sample

36. 4.1.1.8 Origin Metadata Origin Column of Define.xml Multiple Sources
CRF
eDT
Derived
Assigned
determined by individual judgment (by an evaluator other than the subject or investigator)
Protocol
defined as part of the Trial Design preparation
Multiple Sources
Variable-level metadata will list all types separated by commas, eg ‘Derived, CRF’
Value-level metadata will show origin at test level

37. 4.1.1.9 Assigning Natural Keys in the Metadata
Defines ‘Natural Keys’
Keys may include SUPPQUAL
STUDYID, USUBJID, PEDTC, PETESTCD, PELOC, PEMETHOD, QNAM.PEMAKE, QNAM.PEMODEL
Generic test codes rather than bunching

38. 4.1.2.3 Use of “Subject” and USUBJID
No two subjects can share the same USUBJID
Conversely, every subject must retain the same USUBJID throughout the submission (if known)
Format not specified
STUDY-SITE-SUBJID
000001

39. 4.1.2.5 Convention for Missing Values
Missing values represented by nulls
Previously stated that convention used should be specified in the define file

40. 4.1.2.6 Grouping Variables and Categorization
STUDYID
DOMAIN
--CAT
--SCAT
USUBJID
--GRPID
--REFID

41. 4.1.2.6 Grouping Variables and Categorization (cont)
--CAT/--SCAT
Subset groups within a domain
Known about the data before it is collected
Group data across subjects
May have controlled terminology

42. 4.1.2.6 Grouping Variables and Categorization (cont)
--GRPID
Groups data within a subject
Have no meaning across subjects
Assigned during or after data collection
Sponsor defined, not controlled terminology
--REFID
Example, sample identifier for blood sample

43. 4.1.2.7 Submitting Free Text From the CRF
‘Specify’ values for non-result qualifiers
When free-text information is collected to supplement a standard non-result qualifier, free-text value goes into SUPPQUAL.
Reason for Dose Adjustment
Describe
___ Adverse Event [EXADJ]
_[SUPPQUAL]_
___ Insufficient Response
_____________
___ Non-medical Reason

44. 4.1.2.7 Submitting Free Text From the CRF (cont)
‘Specify’ values for non-result qualifiers (cont)
Location of Injection: Other, Specify: ____
Verbatim = UPPER RIGHT ABDOMEN
Option 1: EXLOC=OTHER
Sponsor maintains original CT
Verbatim goes in SUPPQUAL
Option 2: EXLOC=ABDOMEN
Sponsor has expanded CT based on their coding decision of the verbatim text
Option 3: EXLOC = UPPER RIGHT ABDOMEN
Sponsor does not care about CT for this variable

45. 4.1.2.7 Submitting Free Text From the CRF
‘Specify’ values for result qualifiers
Eye Color: Other, Specify________
Verbatim = BLUEISH GRAY
Option 1:
SCORRES = BLUEISH GRAY
SCSTRESC = OTHER
Sponsor wishes to maintain CT
Option 2:
SCSTRESC = GRAY
Sponsor will expand CT based on their coding decision
Option 3:
SCSTRESC = BLUEISH GRAY
Sponsor does not care about maintaining CT

46. 4.1.2.7 Submitting Free Text From the CRF
‘Specify’ values for topic variable
Interventions
Acetaminophen
Aspirin
Other:______
Verbatim will be entered into –TRT
Events
Verbatim entered into –TERM
Findings
Verbatim needs to be coded so that –TEST/--TESTCD are CT and not free text

47. 4.1.2.8 Multiple Values for a Variable
Topic variable (--TRT, --TERM)
Assumed sponsor will split or resolve for their data management procedures
DS is an exception
Covered in
Sponsor chooses primary
Submit others in SUPPQUAL

48. 4.1.2.8 Multiple Values for a Variable (cont)
Findings result variable
Split into 2 rows
EGORRES=ATRIAL FIBRILLATION
EGORRES=ATRIAL FLUTTER
Non-result qualifier variable
Variable value should be MULTIPLE
Individual values stored in SUPPQUAL
AETERM=RASH, AELOC = MULTIPLE
QNAM.AELOC1 = FACE
QNAM.AELOC2 = NECK
QNAM.AELOC3 = CHEST
UNLESS
If one is considered of primary interest, that value can go into the variable, with the others stored in SUPPQUAL
Will reviewer know these are in SUPPQUAL? Document!

49. 4.1.3 Coding and Controlled Terminology Assumptions
‘*’ if no controlled terminology exists
List of the terms if the list is not maintained elsewhere
Name of the external codelist
Full CT Discussion to be held in the future

50. 4.1.4.7 Use of Relative Timing Variables
Introduction to the new SDTM variables
--STRTPT
Examples: " " or "VISIT 2".
--STTPT
--ENRTPT
--ENTPT
Timepoints are not anchored to RFSTDTC and RFENDTC as in --ENRF and --STRF
Valid values in –STTPT or –ENTPT are:
BEFORE
COINCIDENT
AFTER U

51. 4.1.4.7 Use of Relative Timing Variables - Example
If an AE is known to be ongoing during at the end of a subject’s study participation, which is on October 17th, 2008 then:
AEENRTPT = ONGOING
AEENTPT =

52. 4.1.5 Other Assumptions
--ORRES should generally not be populated for derived records
Still not required but highly encouraged
If symbol is collected with original results, for example <10,000 then this gets copied into –STRESC, but --STRESN is null
Also applies to values such as TRACE, 1+, etc.
Discouraging derivations in SDTM
Recommended that this be done in ADaM

53. 4.1.5 Other Assumptions (cont)
If --TEST (except for IETEST and TI.IETEST) values > 40 characters then --TEST should be:
1st 40 characters
Shortened but meaningful version
In either case, if the full text is on the CRF, then link to that from the Origin column. If it is not on the CRF, then link to another PDF which contains the full test name
Also applies to QLABEL in SUPPQUAL

54. 4.1.5 Other Assumptions (cont)
Clinical Significance
Should all go to SUPPQUAL
3.1.1 had EG examples with CS in the results field.
--REAS standard QNAM for reason test was performed

55. 4.1.5 Other Assumptions (cont)
Introduction to the new SDTM variable –PRESP
Indicates that an event or intervention was prespecified on the CRF
Values are Y or null
Situation
--PRESP
--OCCUR
--STAT
Spontaneously reported event occurred
Pre-specified event occurred Y
Pre-specified event did not occur N
Pre-specified event has no response
NOT DONE

56. Domain Models
New assumptions with most tables listing what variables would generally not be added into the domain
Examples moved from Section 9 to Section 6, under corresponding domain table
Variables dropped/added
Variable order changes
Label changes
Assumptions added/clarified/dropped

57. DM
Multiple race should be handled as multiple response for non-result qualifier
Additional race data now goes into SUPPDM, instead of SC

58. CO
No longer restricts the addition of Identifiers and Timing variables
When not related to other domain records

59. SE / SV
Moved from Trial Design to Special Purpose

60. EX
Assumption that EX is required for all studies which include investigational product
Observed by Investigator
Automated dispensing device records
Subject Recall (eg via diary)
Derived from DA (pill count)
Derived from the protocol

61. AE
Removed AEOCCUR
AE is only for AEs that actually occurred

62. CE
Clinical events of interest that would not be classified as adverse events

63. FA Not subclass of the findings domain
Only domain that can use the –OBJ SDTM variable
Previously CF domain (3.1.2 draft)

64. QUESTIONS?