Adjudicating Global Studies - Actelion - 5 May 2015 Philadelphia

Copyright © 2015 Actelion Pharmaceuticals Ltd

ADJUDICATING GLOBAL

STUDIES

5 May 2015 - Philadelphia

Massimo Raineri

Senior Director - Head of Integration

Competency Center - Imperia Site

Head

Actelion Pharmaceuticals

Camilla Maria Mittelholzer

Global Trial Leader, Associate

Director

Actelion Pharmaceuticals

© 2015 Actelion Pharmaceuticals Ltd

Topics:

– Standardize the Adjudication Process Across the Globe

– Effectively Handle Time-Sensitive Adjudications in a Global Setting

– Apply Consistent Endpoint Definitions for Global Studies

– Account for International Differences in Treatments and Standards of

Care

WORKSHOP (B)

ADJUDICATING GLOBAL STUDIES

2


– Short introduction to Actelion Pharmaceuticals Ltd

– Introducing ourselves

– Importance of Adjudication process

– From Camilla Mittelholzer

• Endpoint adjudication – Set up and management in global studies

• Data Integrity – Data consistency and quality in global studies

• What can be done to create consistent definitions for endpoints that are not

too restrictive?

– From Me:

• Our history of Adjudicating Global Study

• Key learnings

• A real example

– All:

• Workshop

AGENDA

3


INTRODUCING ACTELION

4


ACTELION IS A FULLY-INTEGRATED BIOPHARMACEUTICAL

COMPANY WITH INNOVATION AT ITS CORE

ACTELION PHARMACEUTICALS LTD

Actelion Center, Allschwil - Switzerland

Leader in the science and medicine of pulmonary arterial hypertension (PAH)

Imperia Office - ltaly

Founded in 1997 in Allschwil, Switzerland

Total employees:

Drug Discovery

Clinical Development

Marketing & Sales

Support Functions

2‘400

356

594

1‘044

406

Global reach with 30 affiliates worldwide

Over 55‘000 Patients currently treated with an

Actelion medication

Extensive Research & Development portfolio


ACTELION’S PAH FRANCHISE

TREATMENT PATHWAYS IN PAH


PROMISING PROJECTS TO DELIVER FUTURE SUCCESS

LOOKING TO THE FUTURE: OUR PIPELINE

Selexipag

PAH

CadazolidClostridium difficile assoc. diarrhea

Macitentan

Eisenmenger syndrome

Ponesimod

Multiple Sclerosis

Macitentan

CTEPH

Lucerastat

Lipid storage disorders

Macitentan

Glioblastoma

S1P1 follow-up

Immunological Disorders

Phase I Phase II Phase III Regulatory Filing

COMPLETE


INTRODUCING OURSELVES

8


INTRODUCING OURSELVES

9


IMPORTANCE OF

ADJUDICATIONS

10


IMPORTANCE OF ADJUDICATIONS

Methods:

– A total of 35 new molecular entities (NMEs) approved by the US Food

and Drug Administration (FDA) and 88 European Medicines Agency

(EMA) approvals in Europe were included in this analysis (2013, early

2014)

Results:

– An adjudication method was used in phase III development programs in:

• 69% of the NMEs approved in the United States

• 41% of EMA approvals.

Source: Therapeutic Innovation & Regulatory Science I-9

http://dij.sagepub.com/cgi/reprint/2168479015580382v1.pdf

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12



13


SPONSOR

SITE

EXTERNAL ENTITY

EDC

2nd Level EDC

1st Level: Many

Data Sources

ADJUDICATION AS 2ND LEVEL EDC SYSTEM

Two big different scenarios:

• Adjudication on open study,

where time to adjudicate is

crucial

• Any other case:

• Closed study

• Open study, time not critical


ENDPOINT ADJUDICATION

Set up and Management in Global Studies

15 Adjudicating Endpoints in Global Studies05 May 2015


A TEAM EFFORT

GLOBAL QUALITY – ACROSS SITES AND REGIONS

16

QUALITY

Setup –Protocol,

CRF, ICF

Setup –Selection of

Sites and

Vendors

Analysis

Conduct –Trial oversight,

Data reporting,

Trial

Management


Make sure to investigate in case there may be country or site specific

differences in health economics, standard of care, treatment options, type of

subjects to be enrolled etc

Collect regional expertise during the protocol development and include time for

evidence based protocol feasibility before finalization of the protocol

Foresee difficulties and provide specific guidance

Training is key to ensure that the endpoint assessments are correctly and

timely performed

Investigate and assess if cultural differences may play a role in specific study

related subject assessments. Consider and provide training when applicable

If the study is performed in different regions across the world, specific regional

clinical study analyses needs to be considered

ENDPOINT DEFINITION - IDENTIFY COMPLEXITIES

GLOBAL STUDIES – EVENT ADJUDICATION SET-UP

17


The selection of the adjudication experts: consider to include experts from

different regions and countries

− It helps the global understanding while it may add complexity and more

consensus discussions

− Consider similar time zones if possible

An adjudication charter is needed and needs to be reviewed by the experts

Responsibilities and timelines – needs to be clearly defined

− The adjudication committee/board may be able to support the monitoring of

data quality by informing about any weaknesses seen

Adjudication process to be timely set up and available at time of site initiation,

especially important if the endpoint adjudication may alternate subjects treatment

and continuation and study specific assessments.

ADJUDICATION AND MANAGEMENT

GLOBAL STUDIES – EVENT ADJUDICATION SET-UP

18


DATA INTEGRITY

Data consistency and quality in global studies

05 May 2015 Adjudicating Endpoints in Global Studies19


REPORTING, ADJUDICATION & QUALITY CONTROL

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4. Event adjudication,

Quality Control

1. CRF endpoint related

data and any additional

applicable data - To be

reported from site

2. Ongoing

adjudication during

the study

Timely follow-up of source

data review, reporting and

cleaning of CRF data

3. Outcome of the

adjudication


Endpoint data for adjudication - prioritize timely source data verification

– Extra site visit by the CRAs may be needed (depending on the complexity of

the endpoint and adjudication)

Monitor and work to resolve data reporting issues

– In global studies central monitoring is important and close assessment of

outliers

– In case a site is providing unclear data it is important to assess why this

happened and how it can be corrected and avoided for the future

PRIORITIZE DATA QUALITY EARLY

DATA REPORTING FOR GLOBAL STUDIES

Adjudicating Endpoints in Global Studies21 05 May 2015

© 2015 Actelion Pharmaceuticals Ltd22

Subjects randomized and endpoints to be adjudicated

Investigational sites to be monitored

Clinical research associates

Project managers

Data reviewers

Database

FOCUS ON DATA REPORTING AND REVIEW

RESOURCES ESTIMATION AND RISK BASED MONITORING


Lost in translation – Make sure that the definitions, guidelines and timelines are

clear

Study related training is important – Even the best process fails if not

understood

– Especially important for long term studies with several handovers and team

changes – at site, CRA and in-house study team level

– re-training of site and CRA

PRIORITIZE DATA QUALITY EARLY

DATA REPORTING FOR GLOBAL STUDIES



Ongoing Quality Control of the data submitted for adjudication is needed

− Data may change if the subject is ongoing on study treatment, or if not all

study related subject assessments have been performed, or if the

assessments are pending source data verification by the CRA

− If data may change it is important to allow for re-adjudication in case key

variables change

− Definitions regarding what triggers a resubmission needs to be agreed

with the adjudicators

− Plan the reporting and oversight of process well to minimize the need for

readjudication

OVERSIGHT AND CONSISTENCY

ENDPOINT ADJUDICATION – QUALITY CONTROL

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Ongoing Quality Control: Check the adjudicators adherence to the agreed

charter - Ensure consistency across all adjudicated endpoints

OVERSIGHT AND CONSISTENCY

ENDPOINT ADJUDICATION – QUALITY CONTROL




Global Studies and restrictive endpoints

05 May 2015 Adjudicating Endpoints in Global Studies26


Need for global study may depend on:

– availability of patients

– have worldwide acceptable results.

Problems:

– Over recruitments in one region

– Regional variability

Primary endpoints in clinical trials must meet 3 criteria:

1) Clinically relevant

2) Sensitive to treatment effect

3) Measurable and interpretable (you can analyze)

GLOBAL STUDIES AND RESTRICTIVE ENDPOINTS

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Global clinical trials add complexity in case the endpoint may be

affected by:

1) The geographical region

2) The ethnicity

3) Health care systems

4) Availability of treatment(s)


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Parts of a composite endpoint may not be applicable to all participating

countries.

– E.g. if hospitalization is part of the primary endpoint it is important to take

into account that hospital stay might differ according to geographic areas

and health care system (difficult in some regions, depending on social

security program in some, patient’s decision in some others)

It is important to avoid restricting the endpoint to be more applicable for

specific countries

In clinical trials where adjudication is used it may be necessary to blind the

committee to specific trial data or information during the adjudication process

In global studies the option to blind the committee to the geographical

information may be useful. The reviewer may otherwise be influenced by

knowing from which region and country the data is reported.




Definition of endpoints and the need for an independent review committee

depend on:

1) The subjectivity of the primary endpoint

2) The therapeutic area concerned

3) The clinical trial design

4) The need to assess reliability of marginal positive events

5) If a critical assessment is required for adverse event accuracy

NEED FOR AN INDEPENDENT REVIEW COMMITTEE


Source: Therapeutic Innovation & Regulatory Science I-9

http://dij.sagepub.com/cgi/reprint/2168479015580382v1.pdf


Actelion History of Adjudicating Global Studies




ONLINE ADJUDICATIONS SYSTEM IN ACTELION

Year Study Indication Notes

2001 Enable Congestive heart failure (>1600 Patients)

2005 Compass II PAH (Bosentan) Running for 10

years

2008 Conscious II Cerebral vasospasm /

aneurysmal subarachnoid

hemorrhage

With CT scans

images

2008 Seraphin PAH (Macitentan) 3 distinct systems,

closed 2014

2009 Conscious III Cerebral vasospasm /

aneurysmal subarachnoid

hemorrhage

With CT scans

images

2010 Griphon PAH (Selexipag) 3 distinct systems,

closed 2014


I have been involved in the design, development, validation of Endpoint

Adjudication systems and training of Adjudication Committees over 14 years.

I have provided guidance during the set-up, QC step implementation,

adjudication committee training, user support, data submission to Health

Authorities, FDA and EMA inspections of the systems and of the processes.

My experience is limited by the following factors:

– All systems have been managed by the same sponsor (Actelion)

– Only three therapeutic areas covered:

• Congestive heart failure

• PAH

• Cerebral vasospasm / aneurysmal subarachnoid hemorrhage

(POSITIVE AND NEGATIVE POINTS)

MY EXPERIENCE IN THE ENDPOINT ADJUDICATION

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© 2015 Actelion Pharmaceuticals Ltd 3rd Annual DIA Clinical Forum - Nice 2009

WHY CENTRAL AND INDEPENDENT ASSESSMENT?

Accuracy in assessment: high level of expertise

needed

Independency: avoid bias

Homogeneity: centralized committee working

according to a charter


WHY AN ONLINE SYSTEM?

Time to confirm an event as a study endpoint is a

key factor

Amount of data involved in the decision process

Data can change during the adjudication process

before study closure

Users may need interactive tools (generate

Charts, view Radiology / CT images with zoom /

measure / contrast features)



Key Learning

36


Variety of data sources

Time-Sensitive Adjudications

Automate everything that it makes sense to

automate

Possibility to request more data

Management of data changes after event

submission to CEC (Clinical Event Committee)

… FROM 14 YEARS DEVELOPING/SUPPORTING ADJ SYSTEMS

KEY LEARNINGS … / 1

37


Maintain Study Treatment blinded

Embed QC process in the system

Tailor the process to the study

Decision tracker for unplanned or un-frequent scenarios

Other soft considerations

… FROM 14 YEARS DEVELOPING/SUPPORTING ADJ SYSTEMS

KEY LEARNINGS … /2

38


Multiple data sources must be presented:

– CRF / eCRF (Automatic Load)

– External Data (e.g. Central Laboratory, ECG, IxRS) (Automatic Load)

– Documents (Manual Load)

– Images (Automatic Load)

– Coding (MedDRA, WHO DD) (Automatic Load)

Multiple formatting for data presentation:

– List of variables (automatically generated and loaded)

– Case report summaries (automatically generated and loaded)

– Graphic Patient Profiles (self-service)

– Streaming Images (via link to image viewer)

TYPICAL EXAMPLE IN ACTELION

VARIETY OF DATA SOURCES

39


TIME IS CRUCIAL

TIME-SENSITIVE ADJUDICATIONS

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1 event = 1 fire (*)

(*) Message from Griphon Global Trial Leader


REASONS WHY IT IS IMPORTANT


41

Quick reaction on each case from the Sponsor team is important:

– Initiate Selected Source Data Verification

– Data driven monitoring

– A small thing (e.g. fever) can completely change Adjudication outcome

Details can be the key

– Adjudication outcome may drive decisions about patient care

– Number of confirmed cases may drive important milestones (e.g.: Interim

Analysis, Study Closure)

Quick communication channel with site is fundamental



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EXAMPLE

432 events

confirmed

by the CEC

24JAN15

CWE visit

(432 event)

10JAN15

Onset

of 432

Event

27DEC14

4 weeks

+ time defined in protocol for assessment

8 weeks

Last

EOS/SFU

Study Closure

announcement

27JAN15

DB lock

21APR15

1 day2 weeks2 weeks


HOW SOON SHOULD IMAGE BE INTERPRETED?

TIME-SENSITIVE ADJUDICATIONS: REASONS

43

From FDA Clinical Trial Imaging EndPoint Process Standards – Guidance for

Industry – Draft Guidance March 2015:

... The turnaround time by a central image interpretation facility should be

appropriate for the anticipated trial design. For example, prompt image

interpretation may be an important consideration for trial that use centralized

image interpretation as a component of interim analyses ….

Similarly, image interpretation expediency may prove critical when centralized

interpretation is used to help control image quality …


(Importance: See previous slides about Time-Sensitive Adjudications)

Automated tasks (daily execution):

– CRF / eCRF data import

– Generation of Case Report Summaries

Other Automated tasks:

– External Data import (e.g. Central Laboratory, ECG, IxRS)

– Images

– Coding (MedDRA, WHO DD)

… THAT IT MAKES SENSE TO AUTOMATE

AUTOMATE EVERYTHING …

44


There must be a way to communicate from CEC to Sponsor / Site / Monitor

All communication must be tracked

COMMUNICATION CHANNEL FROM CEC TO SPONSOR

POSSIBILITY TO REQUEST MORE DATA

45


Initial review of the internal coordinator

Find balance between

– Submitting complete data

– Do not delay decisions for patient’s care

– Avoid unnecessary resubmission

Training for adjudication coordinators (key role for the study)

MANAGEMENT OF CHANGES

46


Many changes in data may occur, as a consequence of

– Time-Sensitive Adjudications

– Possibility to request more data

We do not want to overload adjudicator’s with need to spot which data points

changed

If we want to implement the idea “Automate everything that can be automated”,

we must find smart tools and techniques

SET THE FOCUS DIRECTLY ON THE WHAT HAS CHANGED

MANAGEMENT OF CHANGES IN THE SYSTEM

47


REASON FOR DATA CHANGES

CRF Entry

Data Management Review

•Logical Checks

•SAE (reconciliation)

•Coding

CEC

Review

Data

Correction or

CRF Entry for

New data

Change in

CRF data


AN EASY CHANGE ON KEY VARS AND CRS


A COMPLEX CHANGE ON THE CRS


MAINTAIN THE STUDY TREATMENTS BLINDING

- Site number

- Information related to study drug dose and interruptiones during

treatment period

- Subset of adverse events (based on below preferred terms). E.g.:

• headache,

• nausea,

• vomiting,

• dizziness,

• myalgia,

• …


Quality Control of Adjudication steps and outcome is important

Evidence of it must be produced in case of inspection

In case of manual trace, documentation can be huge and not easy to handle (23

binders in one of our previous studies)

Electronic process embedded in the system can be recommended

EMBED QC PROCESS IN THE SYSTEM

52


FLOW CHART OF EVENT FINAL QC


Number and “mix” of reviewers

- usually 3 but could be 1,2 or more

- “mix” of reviewers can be required either to balance on the reviewer professional role (i.e. 2 medical experts + 1

radiologist) or to balance between allocated cases

Number, type and structure 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

Process Flow. For instance:

– Rules to define what is an identical decision

– Rules to define need for escalation or consensus meeting

– Possibility to consider minor disagreement on an assessment (or different levels in disagreement) with related

flow management in the process

– Resubmission rules for the coordinator

CONCEPTS ARE STABLE, IMPLEMENTATION IS FLEXIBLE

TAILOR THE PROCESS TO THE STUDY

54


DECISION TRACKER

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GOALS:

• To obtain feedback on the handling of specific adjudication

scenarios for the purpose of:

• Consistency

• Reproducibility

• Reporting in CEC document

• To capture the convention and the rationale

• To facilitate internal QC process

FOR UNPLANNED OR UNFORESEEN SCENARIOS


EXAMPLES OF SCENARIOS

Typically incomplete data or not according to protocol (*):

Patient unable to comply with assessment to be done

Site not yet having the data needed (e.g.: No/limited information on

cause of death available)

(*) e.g. alternative medication not available in country

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DECISION TRACKER

FOR UNPLANNED OR UNFORESEEN SCENARIOS


Interacting with Adjudicators

– They are not normal users

• What is normal for typical EDC users may not be welcome

• They may work in extreme conditions (pub, travel)

– They deserve a special kind of support

• Their time may be really limited

– Training and retraining is important

• Keep it easy

– Avoid automatic mail notification

CEC MEMBERS

OTHER SOFT CONSIDERATIONS

57


Interacting with Authorities during inspections:

– Demo of the system as been requested

– Spotting of tricky cases and full check of audit trail within the Adjudication

system and beyond

– Strong interest on meeting minutes and communications

– Raw data of the Adjudication system requested, including document

packages and “reshaped audit trail”

AUTHORITIES


58


CDISC STANDARD NEEDED?


59

CDISC Europe Interchange 2015 - Congress Center Basel

4 - 8 May 2015

Clinical Endpoint Adjudication: could a dedicated CDISC standard improve

quality?

Presented by Simone Suriano (Ethical GmbH)


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

60

Clinical Trial CDISC Endpoint adjudication CDISC extension ?

Stydy protocol Protocol Endpoint Adjudication Charter ?

CRF forms CDASH Assessment Forms CDASH-like?

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?



A Real Example



A REAL EXAMPLE

CONSCIOUS – 2

Aneurismal Subarachnoid Hemorrhage


ROLES (INSIDE SPONSOR)

Coordinator: Actelion responsible for patient casessubmission to the CEC, document organization and upload.

BatchProcess: Automatic jobs loading data, preparingCRS, detecting changes.


ROLES (OUTSIDE SPONSOR)

Primary Reviewer: 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.


ROLES (OUTSIDE SPONSOR)

Adjudicator: The one who decides when no

unanimity could be reached during a

consensus meeting and completes the

Adjudication Form

Chairman: Is responsible to indicate

whether changes occurring after the subject

case was submitted should trigger a re-

review of the case.


1. Batch Jobs

detecting

cases

2. The

Coordinator

submits ready

cases to a trio of

Reviewers

3. Dr. A Reviews

submitted

patient cases

Process Workflow

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

detecting

changes


4. Decision Dr.A

4. Decision Dr.B

4. Decision Dr.C

Identical

decision?

Yes

No

9. Adjudicator

7. Results

stored on

DB

Unanimity?

Yes

No

8. Consensus Meeting


THE CONTROL PANEL


VIEW IMAGES SECTION EXAMPLE

Inteleview.htm


GRAPHICS SECTION EXAMPLE

Patient_profile.htm


COMPLEX EVENT ADJUDICATION FORM- EXAMPLE


THANKS

72


BACKUP SLIDES

Copyright © 2015 Actelion Pharmaceuticals Ltd

CEC REPORTAN IMPORTANT DELIVERABLE


BACKGROUND: Key filing document, describing entire CEC processes,

outcomes, handling of exceptional cases and individual expert assessments (as

in Seraphin)

PURPOSE: To describe process related to adjudication of MM events and

rational for MM events of special interest (see further slides)

CONTENT: CEC and adjudication system, GRIPHON 3 and 4 incl all CEC crs

and uploaded documents and comments entered by CEC and system

coordinators

PROCESS: Actelion to draft document based on charter, GRIPHON 3 / 4

system, and protocol, reviewed, edited and approved by CEC. Document will

not be finalized prior database-lock, but must be available for CSR.

CEC REPORT – PURPOSE - CONTENT

75


What were the reasons that caused the CEC to disagree with the investigator

about whether an event occurred? (CEC to add sufficient comments);

Comments to be provided also for “NO” in cases where consensus TC was not

needed.

QUESTIONS/ISSUES TO BE CONSIDERED

76

Healthcare

Adjudicating Global Studies - Actelion - 5 May 2015 Philadelphia