1. CDISC Italian-Speaking
User Group Meeting 2008
Milan, 16th May 2008
The Application of SDTM in a
no-profit and disease specific
organization
Angelo Tinazzi
Medical Informatics and Biometry Unit
Early Drug Development SENDO Tech S.r.l. – Milan; ITALY
In Oncology

2. SENDO Background
• No profit organisation acting as a CRO
• Disease Oriented (Oncology)
• Early Drug Development
– Phase I (in humans) for new compounds and for new
combinations (Ib-sponsored or investigator initiated),
Phase II (single indication e.g. Advanced Breast Ca.)
– No involvement in regulatory data submission
?? So why bother about (CDISC) standards ??
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

3. SDTM Pitfalls at SENDO
• Oncology heterogeneity
• New compounds, New Schema à unknown
mechanism
• Phase I in patients
• Customer-oriented
– Internal (Strong Principal-Investigator leadership)
– External (Sponsor)
However some ‘standardisation’ can be applied
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

4. SENDO Customers
• A multinational company imposed its
standards
• A big national company imposed its ‘recent’
(<5 years) standards
• Other companies/biotechs accept SENDO
‘rules’
– Some are starting asking “is your database CDISC
compliant?” …. Is this an appropriate question?
• Common terminology not yet applied
– e.g. several ways for defining AE drug relationship
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

5. Existing standards and projects
in Oncology
Standard Cancer Terminology
• Tumor-extension classification (e.g. TNM)
• Tumor response evaluation (e.g. RECIST
Criteria)
• NCI-AE Common Toxicity Criteria
NCI and CDISC collaboration for Controlled
Terminology CDISC Initiative
• CDISC Review
• Enterprise Vocabulary Services (EVS)
• Cancer Data Standards (caDSR)
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

6. SENDO SDTM Implementation
Back to Origin (2003)
Existing standards
• By module (two digits abbreviation)
• Variable naming convention
– Module abbreviation + Variable abbreviation +
Variable Type
i.e. C for Character, N for Numeric, D for Date
e.g. AEEVEC for Adverse Events Verbatim
• Standard (SI Laboratory Standard Conversion),
Therapeutic (Oncology) and Company standard
terminology
• Tools for Clinical Data Review
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

7. References used in this presentation
• CDISC SDTM Implementation Guide (IG) –
Version 3.1.1
• Study Data Tabulation Model (MOD) - Version
1.1
• All roads lead to SDTM? Which one shall we
take? PhUSE 2007, Paper RA08 (PHUSE)
• Creation of Submission and Analysis Datasets
by following SDTM and ADAM requirements.
PhUSE 2007, Paper RA05 (PHUSE)
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

8. SDTM Implementation – when to
implement?
• Build SDTM entirely in the CDMS (pre)
• Build SDTM entirely on the ‘back-end’ (post)
• Build SDTM using a Hybrid approach (hybrid)
CDMS=Clinical Data Management System
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

9. SDTM Implementation
Other points to consider
• CDMS metadata libraries support
• CDMS flexibility in clinical database updates
• CDMS flexibility in performing complex derivations
• Your Data-Management team ‘language’
• Biostat preferences
• Existing data-management and analysis standard tools
The decision should be driven by the existing company standards regulating
the entire clinical trial process from data collection to data analysis
& PHUSE
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

10. SDTM Implementation – SENDO approach (1)
Hybrid Model
• CDMS Restrictions
• About 70% of SDTM applied in the CDMS
• CDMS data-collection oriented
Standard
Oracle (CT/OC) SAS SENDO-ADAM
SAP/TLG
Other Prop. Db
CDMS “source data” SAS SENDO-SDTM CDISC-SDTM
SDTM-like Programming
Std Med Review Tools
Listings Pt Profiles Other tools
Full CDISC-SDTM +
Sponsor Requirements
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

11. SDTM Implementation – SENDO approach (2)
Apply a Hybrid Model (SDTM-SENDO)
In the CDMS
• SDTM tables (standard domains) naming
• SDTM variables naming (including derived
variables derived in SAS)
• Simple derivations
• If a sponsor plans to submit data to FDA, apply
complete post-processing in SAS
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

12. SDTM Implementation – SENDO approach (3)
SAS Post-processing Mapping (1)
• Direct Mapping
• Complete variables mapping (Rename)
e.g. STDTCàAESTDTC, STDTCàEXSTDTC
& MOD Sect 2.2.5 [Timing Variables]
• Complete derivations Start Date/Time of an observation
• Combine multiple CDMS variables
e.g. datepart variables
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

13. SDTM Implementation – SENDO approach (4)
SAS Post-processing Mapping (2)
• Combine multiple CDMS datasets
– Horizontal to Vertical when required
e.g. vital signs
– Match ‘temporary’ non-standard modules
e.g. chemistry + hematologyàLB
• Standardize format values
• Apply new Formats
e.g. ISO date format
• Creation/Update of Trial Design Datasets
MOD Sect 7.1 [Trial Design Datasets]
Description of key aspects of the planned
conduct of a clinical trial (e.g. arms)
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

14. SDTM Implementation – SENDO approach (5)
Cons of Hybrid Model
• Additional transformations are required therefore
you need:
– Additional Specifications
– Additional Programming Activities
– Additional Validation
• The data-management staff still speaking an other
language (is it a pro or a con?)
• Possible delays in delivering SDTM (and ADAM)
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

15. SENDO map to SDTM – Issues (1)
• CDMS modules (CRF section) that map to one
corresponing SDTM domain
• e.g. Laboratory and Normal Ranges
• SDTM Variables contain decoded text rather
than code (and format/codelist to be applied)
• Other….specify à In SUPPQUAL
& MOD sect 4.4
Non-standard variables not presently included
in the general-observation-class models.
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

16. SENDO map to SDTM – Issues (2)
• Sometimes it can be considered not analysis-
oriented…but this is sometimes due to
programmers attitude
• e.g. vertical vs horizontal structure
• Unclear where endpoints such death and
survival should be collected
• DS?
• ad-hoc module? Findings or Events Class?
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

17. SENDO map to SDTM – Deviations (1)
• Map new variables rather than using SUPPQUAL
& MOD sect 4.4
Non-standard variables not presently included
in the general-observation-class models.
& MOD sect 2.2.5 [Timing Variables]
• --DY variable = 0 Actual study day of Visit/Collection/Exam
in integer days
& IG sect 4.1.4.4
There is no study day 0
• Common terminology not fully-integrated
• Use of code rather than decode
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

18. SENDO map to SDTM – Deviations (2)
• AESEV instead of AETOXGR
• LBCTC (new variables) instead of
LBTOX/LBTOXGR
• Assigned dose-levels in Trial Arms table
& MOD sect 3.2.2
Planned Arms in the trial
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

19. SENDO map to SDTM
Module-specific issues (AE)
• Change in AE-condition in the same visit
– e.g. severity grade (IG 3.1.2–Findings CF module to be applied)
• Multiple Action taken and Drug Relationship for drug-
combination trials
• “Any AE occured” is not allowed
– & IG “When adverse events are collected with the recording of
free text, some sponsors may enter a record into the data
management system to indicate 'no adverse events,' for a specific
subject. For these subjects, do not include a record to indicate that
there were no events unless AEOCCUR is being used to represent
records for non-occurring events. Otherwise, records should be
included in the submission dataset only for adverse events that
have actually occurred”
!!! AEOCCUR removed from IG 3.1.2 !!!
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

20. SENDO map to SDTM
Module-specific issues (EX)
Reasons for treatment change collected in ‘SUPPQUAL’
(EX.EXADJ not applicable for multiple occurences)
EX
SUPPEX
& IG sect 6.1.2 02 2008
01
The Exposure domain model records the details of a
50 5
x
subject’s exposure 51 protocol-specified study treatment.
to 5
x
Interventions (EX) dataset
STUDYID USUBJID DOMAIN VISITNUM EXSEQ EXTRT EXSTDTC
S075MY01 01002 EX 2 2 DRUG1 2008-02-01
SUPPEX (or EM) dataset
STUDYID USUBJID RDOMAIN IDVAR IDVARVAL QNAM QLABEL QVAL
S075MY01 01002 EX EXSEQ 2 RED Dose Reduced 1
S075MY01 01002 EX EXSEQ 2 DELAY Treatment Delayed 1
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

21. Creating a NEW Domain (1)
• Check that none of the existing published
domains will fit the need
• Use existing models as prototype or choose the
general observation class
….How to determine where data belong in the
SDTM, & IG Page 129
• Assign a 2–letter domain code (suggested X_?)
& IG Page 13
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

22. Creating a NEW Domain (2)
Select the SDTM General Observation Classes
Understand the class your domain belongs to
• Interventions
Treatments Change your (my) mind.
or Procedures intentionally administered either specified by
Rather than Analysis oriented:
study protocol or other treatments
(Investigational Treatments, Characteristics
• Patient Conc Medications)
• Events • Treatment Exposure
• Efficacy
Occurences or incidents indipendent of planned study evaluation
occuring before • Safety trial
or during the
(Adverse Events, Medical History) oriented
….‘data-collection’
• Findings
Planned evaluations to address specific questions
(Physical Evaluation, Laboratory)
B
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

23. Creating a new Domain (3)
SENDO-SDTM new modules
• Prior Tumor History
– Prior Systemic Therapies (ST)
– Prior Radiotherapies (PR)
• Tumor Response Evaluation (TAàCA)
• Follow-up (FP)
• Ad-hoc study modules (i.e. lymphoma-non-
hodgkin assessment ad-hoc measurements)
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

24. Creating a NEW Domain (4)
• Add variables as follows (& IG sections)
• Use existing models as prototype or choose the
general observation class
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

25. Creating a NEW Domain (5)
Assign a variable name (& IG Section 10.4)
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

26. Creating a new Domain (6)
Example: Tumor Assessment (CA)
IV SEGMENT 01
05 0 5 10 2007 20
PANCREATIC 01
98 0 5 10 2007 22
NODULE
• Periodic (every 2 months/visits) review of tumor lesions dimension
• Measurement of Tumor-Lesions
– Classified as Target or Non-Target or New
– Description
– Organ location
– Assessment date
– Method used
– Measure (mm)
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

27. Creating a new Domain (7)
Example: Tumor Assessment (CA)
--SPID
Optional Sponsor-defined reference
--CAT
number. define a category of related
Used to Perhaps pre-printed on the
--TEST
IV SEGMENT 1 CRF as an explicit line identifier on a
records. Examples: HEMATOLOGY,
5 0 5 10 2007 20 Concomitant Medications page. to the
--SCAT name, corresponding
Verbatim
CHEMISTRY the test or examination
Used variable, a further categorization
topic to define
--METHOD
1 level for obtain test measurement or
used to a group of or examination
Method of the the related records.
PANCREATIC 98 0 5 10 2007 finding. Examples: Platelet Count,
NODULE 22 Example: DIFFERENTIAL.
Systolic Blood Pressure, etc.
Variables which identify the study, the subject, Variables which describe the timing of an
the domain and the seq nr. of record observation (e.g. date collection)
STUDYID USUBJID DOMAIN CASEQ CASPID VISIT VISITNUM CADTC
S075MY01 01002 CA 1 1.01 BASELINE 1 2007-10-05
S075MY01 01002 CA 2 1.02 BASELINE 1 2007-10-05
Variables, text or number, that describe the results or additional traits of the
observation (e.g. units)
CACAT CATEST CASCAT CAMETHOD CAORRES CAORRESU
TARGET IV SEGMENT 5 1 20 MM
TARGET PANCREATIC NODULE 5 1 22 MM
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

28. SAS Tools supporting SDTM - Proc CDISC (1)
• SDTM 3.1 data validation available in SAS 9.1.3
– Service pack 4 available for download at
ftp.sas.com/techsup/download/hotfix/hotfix.html
– 15 SDTM modules supported
– Various checks on models / variables attributes
(e.g. variables not defined in the domain)
– Various checks on models / variables contents
(e.g. missing values in required variables)
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

29. SAS Tools supporting SDTM - Proc CDISC (2)
Example validating DM dataset
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

30. SAS Tools supporting SDTM - Proc CDISC (3)
Example validating DM dataset
Expected variable warning
Variable AGEU is expected in this domain(DM), but is not present
Permissable variable note
Variable DMDY is permitted in this domain (DM), but is not present
Data Error Incorrect ISO time-units
Variable REFNDTC has incorrect content in observation 4
Incorrect data is 10-12-2008
A time or date component was outside expected range
C
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

31. (SENDO) SAS tools created
• Macro routines library
– Automatic Creation of dataset structures from
metadata definition files (matrix datasets)
– Standard derivation (i.e. date in ISO format)
– Standard terminology application (i.e. Laboratory
Conversion, CTCAE common toxicity criteria)
– Other complex derivations
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

32. Future improvements at SENDO (1)
• Review current terminology
• Full implementation of other SDTM elements to
automatize data-quality/review processes
– Trial Design Datasets
– Relationship (e.g. AEàCM for linking action taken
with corresponding concomitant medications)
• Try to armonize PK and other data from external
providers
• Complete ADAM implementation
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

33. Future improvements at SENDO (2)
Adopt 3.1.2 improvement
e.g. Protocol Deviations (Section 6.2.4.2 IG 3.1.2)
The intent of the DV domain model is to capture protocol deviations that
occured during the course of the study (other than inclusion/exclusion criteria)
as per ICH E3 Section 10.2
STUDYID USUBJID DOMAIN DVSEQ DVTERM DVDECOD EPOCH DVSTDTC
S075MY01 01002 DV 1 NO BLOOD MINOR CYLE01
SAMPLE AT DAY 8
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

34. Conclusion - SDTM (CDISC) Criticism?
• Still SAS v5 transport dataset dependence
– Variable naming (8) limitation
– Character Variable length (200) limitation
• Use of domain abbreviation in variable name
• SDTM is not always suitable for data-entry and
data-validation
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

35. Conclusion - SDTM (CDISC) Alerts?
• Applying SDTM is not just a variable renaming
activity
• Hybrid model is a good compromise
• Keep up-to-dated. If possible be involved in draft
documents review
• Training
• Find the answers using the CDISC public forum
www.cdisc.org/discussions/index.html
AB
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

36. Conclusion - SDTM (CDISC) Requests?
• A model for external peer reviewed data
e.g. Study endpoints such as tumor response
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

37. Conclusion - SDTM (CDISC) Benefits?
• Standardisation improves data-quality
• Tools Re-usability
e.g. data-listings and patient profiles for clinical
data review
• Standardisation is possible even in a
non-commercial (no-profit) organisation
• Academic Organisations should consider it for
better data(knowledge)-sharing
e.g. Meta-analysis
A
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation

38. Thanks and Questions
Many thanks to all SENDO MIBU Staff
• Alessandro Cattaneo
• Anna Compagnoni
• Enrica Paschetto
• Sonia Colombini
Angelo Tinazzi, SENDO Tech S.r.l.
Medical Informatics and Biometry Unit
Via Visconti di Modrone 12
20122 Milano
tinazzia@sendo-org.it
CDISC Italian-Speaking Usergroup Meeting 2008 – Angelo Tinazzi (SENDO Tech S.r.l.)
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The Application of SDTM in a no-profit and disease specific organisation