CDISC Europe Interchange 5-6 May 2015 - Basel CH - Clinical Endpoint Adjudication: could a dedicated CDISC standard improve quality?

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2. © CDISC 2015
Presented by Simone Suriano
Contact info:
Ethical GmbH
Wartenbergstrasse 40,
CH-4052 Basel - SWITZERLAND
info@ethical.ch - +41 (0) 61 271 30 30
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Clinical Endpoint Adjudication:
could a dedicated CDISC standard
improve quality?

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Topics
• What is Clinical Endpoint Adjudication?
• In which trials is it used?
• Typical adjudication process and players
• Adjudication Data Submission
• Proposal for a standard approach
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Clinical Trial vs. Adjudication
Study Protocol
Patient Data
CRF data collection
Study coordinators, Monitors,
Investigators…
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Clinical Endpoint Adjudication Charter
Adjudication information package
(data related to the patient from different sources
including documents, images, videos)
Adjudication form assessment
Process coordinators, Reviewers,
Central Evaluation Committee (CEC)
Chairman…
Rules of
the game
Playground
Goal
Players

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Trials where adjudication is used
• It is used in trials where an endpoint is determined by clinical
or radiological examinations requiring interpretation by
expert(s) rather than by means of pre-defined laboratory
measurements or other objective / measurable methods
• More generic: when an endpoint assessment is solely based
on the opinion of a rater / assessor, i.e., is subject to
personal interpretation
• A more scientific description of use scenarios can be found in the
article “An Overview and Analysis Regarding the Use of
Adjudication Methods in EU and US Drug Approvals” freely
available on DIA Journal (dij.sagepub.com) at the following link:
http://dij.sagepub.com/content/early/2015/04/21/2168479015580382.f
ull.pdf?ijkey=pXnQG9hhgzmG59u&keytype=finite
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Adjudication – the players (an example)
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Coordinator: Sponsor responsible for patient cases submission to
the CEC, document organization and upload, Quality Control.
Batch Process: Programs loading data, preparing CRS (Case
Report Summary), detecting changes (optional)
Primary Reviewer(s): The CEC member who makes the primary review
of a subject case and completes a CEC Form.
Consensus Reviewer: The CEC member who leads the
consensus meeting and completes the Consensus Form.
Chairman: Is responsible to indicate whether changes occurring after the
subject case was submitted should trigger a re-review of the case.
Adjudicator: The one who decides when no unanimity could be reached
during a consensus meeting and completes the Adjudication Form

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1. Batch Jobs
or Coordinator
detecting
cases
2. The
Coordinator
submits ready
cases to a trio of
Reviewers
3. Dr. A Reviews
submitted
patient cases
3. Dr. B Reviews
submitted
patient cases
3. Dr. C Reviews
submitted
patient cases
4. Decision Dr.A
4. Decision Dr.B
4. Decision Dr.C
5. More Data
Needed
6. Batch
Jobs or
Coordinator
detecting
changes
Adjudication – process example
(Centralized Online Process)
…continue on next slide…

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Adjudication – process example
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4. Decision Dr.A
4. Decision Dr.B
4. Decision Dr.C
Identical
decision?
Yes
No
7. Results
stored on
DB
Yes
No
8. Consensus Meeting
9. Adjudicator
Unanimity?
…completes previous slide…

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Adjudication – the charter
- Number and “mix” of reviewers
- usually 3 but could be 1,2 or more
- “mix” of reviewers can be required. Mix can be on the reviewer professional role (i.e. 2 medical experts + 1
radiologist) or mixing and balancing between cases a set of “equivalent” reviewers
- Number and type of adjudication forms
- could be specific for each case type – one for hospitalization, one for worsening, one for death, etc…
- or one form only for all cases;
- Rules to define concept/rule
- Rules to define concept/rule
- Resubmission rules for the coordinator
- Possibility to consider minor disagreement on an assessment (or different
levels in disagreement) with related flow management in the process
- The kind of process (centralized/distributed; paper/electronic/web based)
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Identical
decision?
Unanimity?

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Adjudication – the data
- Main source is usually a subset of CRF data - coming from paper or EDC / Medical
Records / Source documents / Patients Profiles systems / ePRO / etc… (with related
“data quality” management issues and the possibility to need a process which handles
re-submissions to reviewers.
- External providers (Laboratory data and similar) – sometimes rendered in graphical
format
- Other documents related to the patient/case
(hospitalization/discharge summary,
death certificate, diagnostic results/reports,
scorecards, etc…)
- Images / videos
(ECG, tomography, RMN, echography,
angiography, gastroscopy, etc…)
- Full or specifically designed CRS (case report summary)
- Many different formats
(mainly scanned PDFs,
many specific image formats – DICOM, jpeg, others…)
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Adjudication – other aspects
- Not always the “full” set of events to be submitted can be foreseen at the
beginning of the study
- Blinded/unblinded adjudication process
- Multiple submission of the same case (not a “must”, but an added value
when dealing with potential data quality issues)
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Adjudication – the assessment
- The final assessment is the result of the matching of each
reviewer’s assessment following the “rules” stated in the
charter
- The final assessment can be represented as a dataset
with the content of the “adjudication form” filled-in by the
reviewers:
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Adjudication – data submission
• At the end of the process and upon study closure, data
have to be sent to regulatory authorities.
• Data to be presented includes:
 The data presented to the adjudicators on the last “submission round”
for each case (including all kind of data: variables from CRF/EDC,
documents, images…);
 The final assessments on the last submission round for each case
AND for each reviewer;
 The final assessment result for each case
 Full audit trail / history of submissions and assessments
• Currently I can find two main approaches to represent
assessments results in electronic format:
 With a custom / legacy data format decided directly with the receiver;
 Using a CDISC-like approach adapting the “free” available domains
(i.e. XX, XY, ZX…) to represent the final result of the assessments
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The proposal to improve standard approach
• There is a lack of “standard” approach in many phases
of the process
• Also where CDISC approach is used to submit data in
the “free” domains, this is not “really” standard…
Proposal: to build a more standard approach to organize
and harmonize the process could be a benefit
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Clinical Trial CDISC Endpoint adjudication ?
Stydy protocol Protocol Endpoint Adjudication Charter ?
CRF forms CDASH Assessment Forms ? - CDASH-like, specific per TA?
CRF data SDTM Assessment Data ? - SDTM-like?
Adjudication submission package:
- data ? - SDTM-like? LAB-like?
- folder structure ? – eCTD-like?
CT Analysis data ADaM Endpoints assessment Analysis data ? - ADaM-like?
Terminology Controlled terminology Terminology ? - Controlled terminology?
...Other I am not aware of... ...Other I am not aware of... ?

15. © CDISC 2015
Special thanks to:
• Massimo Raineri - Senior Director, Head Clinical Development Integration
Competency Center – Actelion Ltd.
• Beat Widler – Quality Assurance and Head of CSV – Ethical GmbH
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Questions (& answers?)
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