DIA 2019 presentation by Dr. Jules Mitchel with Michelle Eli (Lilly) and Tom Haag (ex-Novartis) based on their experience with Lilly collaborating on Target Health's paperless clinical trial system.

1. 1
A Pharma/CRO Partnership in the Design and Execution of
Paperless Clinical Trials from eICF to Database Lock –
Lessons Learned
Michelle Eli
Clinical Project Management Advisor, Chorus
Eli Lilly and Company

2. 2
Meet the Presenters
Michelle Eli
Clinical Project
Management Advisor,
Chorus
Eli Lilly and Company
Jules Mitchel
President
Target Health Inc
Tom Haag
Principal Consultant
Cardinal Solutions
Consulting, LLC

3. 3
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Disclaimer – Content Slide

4. 4
You can never go 100% paperless.
REALITY: Maybe not 100%, but you can get really close.
Regulators won’t go for this.
REALITY: Not true
Sites will HATE not having paper.
REALITY: This was not our experience.
This will never work outside the US!
REALITY: Not true
You can’t perform source data verification (SDV) if you have no source
documents!
REALITY: You can and a lot of it can be done virtually
The Paperless Clinical Trial-Perception vs Reality

5. 5
The Paperless Clinical Trial-The Components
DDC (Direct Data Capture or e-
source)
e”Other”
eTMF (Trial Master File)
eICF (Informed Consent)
eISF (Investigator Site
File)

6. 6
Sponsor/Pharma Perspectives
• Real time access to data enables timely identification of potential
data issues and/or protocol deviations allowing for immediate action
to be taken.
• True implementation of risk-based monitoring, together with Direct
Data Capture (DDC) enables the team to focus on critical data.
• Regulatory Readiness is simplified with electronic Investigator Site File
in the same eTMF system with restricted access to sites and monitors
only.
The Paperless Clinical Trial-Why Go Paperless?

7. 7
Site Perspectives
• Focus on seeing patients and not transcribing data from paper
source documents
• Access to only the current Informed Consent Form (ICF; older
versions become unavailable with eICF)
• Reduce the chance of consenting with incorrect version
• Reduction in or elimination of resources needed to create
protocol-specific source documents
The Paperless Clinical Trial-Why Go Paperless?

8. 8
Site Perspectives (cont.)
• Fewer queries given that data transcription is lessened or
eliminated
• No longer need to accommodate multiple monitoring visits
(and then reorganize source documents if monitor re-files
papers incorrectly)
• Real time query resolution thus eliminating/significantly
reducing backlog and back and forth resolution
communications
• Continuous access to and control of electronic source data with
clear audit trail readily available for sponsor/regulatory
authority audits
The Paperless Clinical Trial-Why Go Paperless?

9. 9
The FDA guidance on eSource includes the following:
“Sponsors should include (e.g., in the protocol, data
management plan, or investigational plan) information about
the intended use of computerized systems used during a
clinical investigation, a description of the security measures
employed to protect the data, and a description or diagram of
the electronic data flow.”
The Paperless Clinical Trial- FDA Perspective

10. 10
The Paperless Clinical Trial- FDA Perspective
ICH E6 R2 contains the following in support of eSource/DDC
detail being included in the Protocol:
• 5.0.1 Critical Process and Data Identification: During protocol
development, the sponsor should identify those processes and
data that are critical to ensure human subject protection and
the reliability of trial results.
• 6.4.9 Requirements for Protocol Content include the following:
The identification of any data to be recorded directly on the
CRFs (i.e. no prior written or electronic record of data) and to
be considered to be source data.

11. 11
The Paperless Clinical Trial- EMA Perspective
The EMA Reflection Paper on eSource at Topic 2: Creation,
modification and transfer of data includes the following:
“The location of source documents and the associated source data should
be clearly identified at all points within the capture process. (Requirement
11, ICH GCP 6.4.9) The protocol should identify any data to be recorded
directly into the CRFs that is considered to be source data. A detailed
diagram and description of the transmission of electronic data should be
provided in the protocol. The source data and their respective capture
methods should be clearly defined prior to trial recruitment (i.e. in the
protocol or study specific source data agreement). The sponsor should
describe which data will be transferred, the origin and destination of the
data, the parties with access to the transferred data, the timing of the
transfer and any actions that may be triggered by real-time review of those
data.”

12. 12
The Paperless Clinical Trial
EMA eSource DDC Qualification Opinion
The EMA issued a Qualification Opinion on DDC in 2018:
– “[eSource] presents challenges but no theoretical obstacles: if it
can be designed to meet all requirements for ICH source data
and (national) requirements regarding the EMR maintenance,
then it could be compliant.
– Data privacy is one of the main GCP principles. According to
the Declaration of Helsinki, it is the duty of physicians who are
involved in medical research to protect the privacy, and
confidentiality of personal information of research subjects.”

13. 13
The Paperless Clinical Trial-Regulatory Takeaways
The Regulatory Signals are clear:
• Put it on the table up front; discuss in scientific meetings; focus
on GCP!
• Include data chain of custody and dataflow in protocols;
transparency and understanding is key.
• Ensure that the site has control of (and continuous access to)
the patient data.
• Registration packages containing studies with DDC have been
approved in Australia, EU, and US.

14. 14
The Paperless Clinical Trial-Data Flow (EMA)
• Study data are captured by DDC Tool
(blue) and directly transferred to the EMR
(green); data is source data (ICH150 GCP
E6 (R2) 4.9.0 and 8.3.13).
• A faithful copy of the DDC tool data is
mapped and filtered to ensure that only
pseudonymised data and data defined per
protocol is uploaded to the DDC tool
database (red).
• Site specific data is transferred to the
sponsor (violet) and to the investigators
TMF (green) to enable verification of
accuracy, completeness, legibility, and
timeliness of data reported to the sponsor,
analogues to the requirement of a CRF
copy (ICH-GCP E6 (R2) 4.9.1, 8.1, 8.3.14
and 8.3.15).
• It is the sponsor’s responsibility to ensure
all data transfers take place and are
sufficiently validated and all audit trail
information is kept throughout all transfers
(ICH GCP E6 (R2) 5.5.3)

15. 15
The Paperless Clinical Trial-Keys to Success
Sites
• Engaged staff
• PI/Management support
• Sponsor support
• Understand Regulatory
Viewpoint (DDC ≠ 483)
• Understand Site Value
Proposition
• User Friendly DDC System
Regulators
• Assurance that site has
control of and access to all
patient data
• DDC Transparent Sponsor
Communication Data
Quality
Pharma/Sponsor
• Innovative Culture
• Management Support-
Understand Value Proposition
• Lean Drug Development
Mindset
• Clear Process for DDC and
Data Chain of Custody Flow in
Protocol
• Strong partnership with sites
• Appropriate Oversight
• Understanding of Regulatory
View on DDC

16. 16
Trial Overview
• Phase 2a Study
• Treatment period: 24 weeks
• 120 Patients across 13 Investigator sites
• 10 US and 3 Japan
• Study Data Collected
• Patient visit data (AEs, Concomitant Meds, Demographics, Scales, etc.)
• Lab data (Safety, PK, PD)
• Patient Reported Outcomes
Case Study-Eli Lilly and Company

17. 17
Case Study-Paperless Components
DDC (Direct Data Capture or e-
source)
ePRO
eTMF (Trial Master File)
eICF (Informed Consent)
US Only
eISF (Investigator Site
File)

18. 18
Case Study-Monitoring and Database Lock Metrics
Sites Site Visits
(over approx. 13 months)
Central Monitoring Time to DBL from LPV
US 1 6 12
Planned duration-28 Days
Actual duration-10 days
US 2 4 6
US 3 4 9
US 4 3 13
US5 4 15
US 6 4 15
US 7 4 16
US 8 4 14
US 9 3 7
US 10 3 6
Japan 1 8 33
Japan 2 9 32
Japan 3 7 24
TOTALS 63
(US Avg=3.9; Japan
Avg=8)
202
(US Avg=11.3; Japan
Avg=30)

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Case Study-Lessons Learned
Take the time, upfront, to walk sites through the system and help
them understand how DDC will be incorporated into their workflow.
– Some paper source documents may be needed. DDC enables source
designation, which enables monitors to know exactly what SDV needs to be
done.
– Site feedback was incorporated into system revisions
Evaluate site’s internet connectivity in exam rooms and laptop
availability. Be prepared to provide laptops.
Sites like this approach!
Having monitors who are very familiar and comfortable with the
DDC system to coach/help the sites is essential.

20. 20
Case Study-Lessons Learned
Having a robust source mapping document/dataflow is key from
multiple standpoints (communication within study team, audits).
Real time access to data was vital to quickly identifying and
rectifying site data collection issues.
Database lock 7-10 days post Last Patient Visit (or faster!) can be the
norm for this type of study.
Close collaboration with DDC vendor, sites, and sponsor is essential.
This isn’t difficult. Be flexible and listen…it’s a continuous learning
process.

21. 21
Key Takeaways
FDA and Global Regulators have approved new drugs with DDC data
packages and welcome DDC discussions.
DDC saves time and money without compromising data quality.
Data oversight, traceability and control is important for investigators,
sponsors, and regulators.
DDC isn’t new and should be considered as a key component to
streamlined drug development.
There is a learning curve, but uptake can be quick with a user-
friendly DDC system.

22. 22
Jules Mitchel
President
Target Health Inc
Tom Haag
Principal Consultant
Cardinal Solutions Consulting, LLC
Michelle Eli
Clinical Project Management Advisor, Chorus
Eli Lilly and Company
Thank You
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