eTMF/eISF

IntegrationChallenges and Benefits

Kathie ClarkWingspan TechnologyVice President Product Management

1

Agenda

2

• Definitions: (e)TMF and (e)ISF• Segregation and Control of the (e)ISF• Site Document Challenges: eTMF and eISF• Benefits of Integration• Integration Pitfalls

Definitions: TMF and ISF

3

Trial Master File Investigator Site FileThe Trial Master File (TMF) is the collection of documentation that

allows the conduct of the clinical trial, the integrity of the trial data and the compliance of the trial with GCP to be evaluated.

Held by (or for) the sponsor organization.

The Investigator Site File (ISF) is the

set of documents that must be held by the site for a similar purpose.

And… EU Regulation Article 58 requires that "the

sponsor and investigator shall archive the

content of the clinical trial master file for at least 25 years after the end of the clinical trial."

Segregation of eTMF and eISF

Health Authorities all stress that some documentation held by the sponsor must not be sent to the site and vice versa

FDA

“It is essential to segregate some documents that are generated or held by the sponsor (eTMF) from those of the investigator (eISF) and vice versa as some documentation held by the investigator should not be provided to the sponsor, i.e. documents that would result in breach of subject confidentiality.”

MHRA

“In organising the TMF, it is essential to segregate those documents that are generated or held by the sponsor of the trial from those of the investigator, as some documentation held by the investigator should not be provided to the sponsor…. due to subject confidentiality issues [and because] providing this to the sponsor would remove the investigator’s control.”

TMF – ISF Document Overlap

5

5

Trial Master File(Sponsor)

Investigator Site File

Ownership of the (e)ISF

6

“The investigator should retain control of the documentation

contained in the investigator site file. The investigator site file should never be sent to the sponsor organisation except in sponsor-investigator situations.”

“The documentation in the investigator site file will contain source documents - for example, subject screening and identity logs, consent forms, drug accountability records – and control of these must

remain with the investigator... A situation where all the site records are sent to the external sponsor for uploading onto an eTMF system, which the investigator then accesses via a portal, would breach this requirement.”

Challenges of eTMF and eISF

Each system has its own challenges that can decrease user acceptance, compliance, efficiency, and inspection-readiness. Some can be addressed by eTMF/eISF integration.

eISF

• Site adoption

• Need for additional scanning of documents that would have been left as paper documents

• (sometimes) inability to apply electronic signatures

• Version control / access to updated versions

eTMF

• Poor insight into site status

• Extensive reliance on email / manual download of site documents; repeated requests

• Need to reconcile TMF documents with documents held at the site

• Significant lag between document finalization and availability in eTMF (especially for drug shipment)

How Many Documents Per Site in TMF?

8

Our research shows that the average site has about site-level documents in eTMF*

Of those, 83% need to be

reconciled at the site

And some sites in our eTMFs have

over 2000 documents

128

* Exclusive of Subject Documents

Most Common Site Documents in TMF

9

Our research shows that the following document types are those most commonly

seen at the site level in eTMF – most also appear in eISF.

0

2

4

6

8

10

12

14

16

Training

GCP, IRT, EDC, Study-Specific, etc.

IRB/IEC

Membership, compliance submissions, approvals,, notifications, etc.

Monitoring

MVRs, follow-up letters, logs…

CVs

Principal Investigator, Sub-Investigator, others (sometimes multiple formats)

PerSite:

What Can Integration Do?

Decrease Errors• Avoid multiple uploads of the

same document, out of synch versions, and transfer by email.

Increase Timeliness

Improve Insight

Decrease Paper

• See which documents have been requested and when, which are in process, which are missing…

• Make use of electronic signatures

• Encourage sites to create electronically by providing templates

• Transfer documents from one system to another immediately upon finalization.

Increasing Efficiency with Integration

• Auto-file sponsor distributed documents as soon as they are approved

• File documents in a structure that makes sense to site

• Eliminate email distribution or hard copy distribution

• Push milestone-based requests for documents to sites

• Monitor the timely filing of requested documents

• Ensure sponsor awareness of unplanned documents (not requested from site) such as protocol deviations or certain ethics communications

• Reduce document handling from former process of print-sign-upload-check-collect paper to just signing

• Reduce paper storage both at site and at sponsor

• Enable CRAs to review ISFs and other site-based documents remotely so they can focus their onsite visits on helping the site

• Ensure that both sponsor and site are working from the same document versions

Automatic Delivery to Site

Automatic Requests to Site

Receipt of Unplanned Documents

Reduced or Eliminated

Reconciliation

Electronic

Signature

Example: Handling the 1572

Compare the efficiency of processes when different options are in place:eTMF, no eISF Non-integrated eTMF & eISF Integrated eTMF & eISF

1. Site fills out 1572 after CRA prompting

2. Investigator signs (wet ink)3. Site or CRA scans4. Document uploaded to

eTMF5. QC process completed (may

result in the need for corrections and repeating 1-4)

6. Document finalized in eTMF7. CRA collects wet-ink signed

document and delivers for archiving

8. CRA reconciles ISF and eTMF documents

1. Site fills out 1572 and uploads to eISF after CRA prompting

2. Investigator signs (wet ink or eSignature)

3. CRA obtains document by download or email

4. Document uploaded to eTMF

5. QC process completed (may result in the need for corrections and repeating 1-4)

6. Document finalized in eTMF7. CRA collects wet-ink signed

document and delivers for archiving

8. CRA reconciles ISF and eTMF documents

1. Site prompted to upload 1572 – automatically transfers as draft to eTMF

2. QC process completed (may result in the need for corrections and repeating 1)

3. PI receives and completes eSignature task

4. Document finalized in eTMF and eISF

Integration Pitfalls

Most pitfalls are related to replicating the paper process

2

3

4

5

1

Manually push and pull documents to and from the separate repositories.

Force sites to take on your TMF organizational or folder structure.

Force sites to enter excessive (any?) metadata to support TMF.

Feel compelled to reconcile.

Require too many signatures.

You might… Instead…

Create rules so that documents are automatically and reliably transferred.

Retain folder structures familiar to sites.

Enrich metadata when documents enter eTMF.

Rely on the electronic systems to ensure that sponsor and site documents are synchronized.

Review and streamline your signature practices.

14

Thank You!

Kathie Clark

Vice President, Product Management

Wingspan Technology, Inc.

kclark@wingspan.com