Signature Practices and Technologies for TMF An Industry Overview

Kathie ClarkWingspan TechnologyVice President Product Management

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Agenda

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• Review of Guidance and Regulations• Research Approach• Results

o What types of documents are signed?o Why are documents signed when regulations don’t require

signatures?o What are practices around hard copy retention / destruction?o Opportunities for streamlining processes

Signature Regulations (1)

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Before permitting an investigator to begin participation in an investigation, the sponsor shall obtain…A signed investigator statement (Form FDA-1572)

For all device studies, the sponsor should develop an investigators agreement…sponsor should have all investigators sign the agreement prior to participating in the study.- 21 CFR 312.53(c)

1572 / Statement of Investigator

SIGNED PROTOCOL AND AMENDMENTS, IF ANY - ICH GCP 4.5.1

The investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm agreement.- ICH GCP 8.2.2

Protocol and Amendments

A written, dated, and signed agreement between two or more involved parties…- ICH GCP 1.17

SIGNED AGREEMENT BETWEEN INVOLVED PARTIES - ICH GCP 8.2.6

Contract

Signature Regulations (2)

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SIGNED, DATED AND COMPLETEDCASE REPORT FORMS (CRF) [ORIGINAL WITH SPONSOR]- ICH GCP 8.3.14

Case Report Forms

The forms are to be signed and dated by the chief financial officer or other responsible corporate official or representative of the applicant. - 21 CFR 54.4(a)

Financial Certifications & Disclosures, FDA 3454 / 3435

Where signatures of the principal or coordinating investigators are required by regulatory authorities, these should be included in appendix 16.1.5 (see Annex II for a sample form). Where these are not required, the signature of the sponsor’s responsible medical officer should be provided in appendix 16.1.5. - ICH E3 Section 6

Clinical Study Report

What’s NOT Required (Examples)

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Signature Page (optional) - ICH GCP 7.5

Investigator’s Brochure

22. Are CVs required to be signed and dated? No. FDA regulations do not require a CV to be signed and dated. The investigator’s signature on the 1572 is sufficient to attest to the accuracy of the CV or other statement of qualifications submitted with the 1572. - FAQs – Statement of Investigator Form FDA 1572)

[Transcelerate form includes a signature field.]

CVs

DA has no preference as to how this information is collected from investigators. Sponsors have the flexibility to collect the information in the most efficient and least burdensome manner that will be effective…if the study sponsor has provided the clinical investigator with a form to collect the financial disclosure information, the investigator should follow the sponsor’s instructions for completing the form, including whether the copy with the original signature is sent to the sponsor or maintained by the investigator.- Research, First Clinical Research FDA GCP Q&A

Financial Disclosure from Investigators

What’s NOT Required (Examples)

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“The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.” - ICH GCP 4.1.5

Delegation logs are not addressed in FDA’s Federal Regulations (21 CFR 312 and 812); therefore a delegation log is not a federal requirement.

Delegation Log

Signature Sheet / Log

“To document signatures and initials of all persons authorized to make entries and/or corrections on CRFs.” [21 CFR does not mention this document.]- ICH GCP 8.3.24

[Transcelerate form includes a Principal Investigator’s End of Study Declaration]

MHRA GCP Guidance on Signatures

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“The documentation in the TMF should be

complete, legible, accurate, unambiguous

and, where appropriate signed and dated.

Signatures on documents are recommended

only where it adds value; many documents

require wet-ink signatures as a result of

internal written procedures, without clarity

on what the signature is actually for. Some

documents should be expected to be signed

as part of GCP requirements (for example,

the clinical trial protocol).”

Phase 1: Signature Interviews

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Conducted with titles such as Directors/ Manager of eTMF, Start-up, Document Management, Records Management, Quality, plus a few CRAs

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LargePharma

CRO MediumPharma

SmallPharma

Key Questions

What documents do you sign?

Do you collect paper or leave at sites?

What paper copies do you keep?

How could your signature related processes be more efficient?

Why do you sign documents when the regs don’t require it?

Phase 2: Signature Survey

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Developed based on Interview Findings Completed by 27 participants

Typical Titles

• Director, Quality and Compliance

• Director, TMF Process Management & Quality Control

• Director, Clinical Document Management

• Head Clinical Operations

• Clinical Document Specialist

• Senior CRA

• Manager, Clinical Affairs

• Clinical Documentation and System

Participants’ Use of eTMF

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Note: No Digital Signature Use

Reported

Key Findings – Signature Philosophy

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• Some of the interviewees initially said that they mainly signed documents with regulatory requirements for signature, but later discussion revealed that they sign more…

• A number of participants said they had planned or completed an evaluation of what they are signing

Assessment of Signature Practices?

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02468

10This assessment yielded the justification exec leadership required to move forward qualifying/vetting/selecting a validated eSig

I reviewed the ICH Guidelines and brought them to management for consideration, but nothing changed.

Yes - we are in the process of trying to modify our current practice so we are not as conservative

Assessment revealed many un-required signatures, though change has been slow

My company was overly cautious and required many document signatures beyond those required by regulations, many original wet ink

Key Findings: Documents that are Signed (Without Regulatory Requirement)

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Do your policies require signatures for:

No

Yes, Wet InkSignature

Yes, eSignature

Varies

Why are documents signed when there is no regulatory requirement?

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• SOPs require signatures.

• Assume past habits dictate current practices – Heavy dose of tradition.

• Having signed the document means that signatories take responsibility that the contents has been reviewed and approved and is correct.

• Adds validity and shows something is final. For correspondence, especially monitoring follow-up letter, the feeling is that a signature shows that this is final.

• Our QA department requires it!

• For organizations with paper TMF, no other real way to demonstrate oversight and approval.

• Proof of oversight.

• We are conservative!

Key Findings – Retention of Signed Originals

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• We instruct CROs to leave ALL signed site documents at the site…but still occasionally get packs of paper.

• Sites sometimes have a policy that they don’t route originals.

• Conservative process at our company. We are moving forward to collect only a few documents. All others will begin to remain at site.

• 1572s mostly signed wet ink and originals retained at site.

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Do sites retain the signed originals for the following types of documents?

Site Retains

We Collect

Document NotSigned

Varies

Don't Know

What does Guidance say?

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Only documents where GCP mandates that sponsor maintains original:

Why then? Some answers given:• Quality group still considers best practice to ensure authenticity by collecting original wet ink

document• Concern about site retention practices• There isn't always a clear process/reason on which original documents should remain at the site

and why some return in-house• Inspection concerns

Key Findings: Destruction of Paper

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New policy – no need to retain any paper for documents uploaded to a validated eTMF by an authorized user.

Officially, we discard everything. Unofficially, we are still retaining signed paper (both internally and externally signed) – will re-evaluate at end of trial.

[Company] did a lot of research when determining what paper to retain and found that concerns about certain countries requiring paper were greatly exaggerated. Only a few countries (South Africa, New Zealand, China for documents originating in China) still require paper and we leave it to the local affiliate to handle by retaining paper or printing.

We scan and save copies of all TMF documents on file. The electronic copies are not controlled in any way.

Without an e system in place originals are kept by most of our clients. … Many even keep a copy for "just in case”.

Key Findings: Destruction of Paper

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MHRA GCP 10.5.5 Destruction of Original Paper Records

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The use of an eTMF would be considered as a prerequisite to the sponsor's being able to destroy paper records and reduce storage requirements. The Clinical Trials Regulation does not consider the transfer of documentation to other media, but does require the documents to be readily available, complete and legible, and contain traceability of any changes made. EudraLex Volume 1 guidance states that sponsors should ensure that essential documents are not destroyed before the end of the required retention periods; however, transfer of the document to an eTMF repository could enable earlier destruction of the paper original.The eTMF system would need to have all the characteristics as defined above, such that there is confidence on inspection that the eTMF is complete and the documents are authentic copies. Experience of eTMFs to date has not yet provided sufficient evidence that inspectors would not need to request some original paper records for inspection, and thus early complete destruction of such records is not currently recommended or should only be undertaken on a risk-adapted approach.

MHRA GCP 10.5.5 Destruction of Original Paper Records

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• A duplicate paper TMF need not be retained; the reasons for this include the following:

o A document may only have existed and been used in an electronic format (for example, a spreadsheet used for OC of edit check programs).

o A paper document may be a copy of an original located elsewhere (for example, investigator's signed CV).

o Documents do not have wet-ink signatures, thus the electronic version is an exact copy of the paper version that has been in the TMF (provided there are no additional annotations made, handwritten or otherwise - for example, receipt stamps, fax machine header).

• This indicates that the eTMF would contain some documents that are more likely to have the original paper copy requested than others, such as agreements with wet-ink signatures and signed letters. The current recommendation is to undertake a risk assessment in order to decide which documents do not need to be retained on paper, particularly focusing on whether or not the paper version could be obtained upon request (for example, reprinted or obtained from another location).

For advise on this topic: consult The Framework for The Destruction of Paper

Site Signature Perceptions

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Some sites refuse to use signature capabilities – possibly due to legal issues (not approved by their legal depts.), or because they have already adopted another technology.

We probably would not accept an eSigned document using a site’s system due to validation concerns.

Cost is primary issue preventing us from extending electronic signature credentials to site users.

What factors increase the time and cost associated with signature processes?

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• Courier costs and risk of loss/damage. But leadership teams don’t seem worried about having to pay for FedEx – what will motivate them to change practices?

• Excessive resources touching a document (e.g., coordinator 'preparing' documents for investigator to sign, investigator signing, then coordinator packaging and shipping out signed document on one end; and reg reviewer, then scan tech / file room clerk on other end)

• Existence of multiple 'originals' for plans and similar documents requiring multiple approvals (often re-assembled by scanning)

• Anything that still requires wet ink signatures slows things down – people may be OOO, etc..

• File size issues in emailing document distribution

What factors increase the time and cost associated with signature processes?

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• Finalization of a document could be delayed, due to an approver not having access to a printer and scanner

• Lost documents having to be re-sent, especially when CRO /3rd parties are involved

• Document review not being completed when documents collected, then being found during an audit

• Allowing key documents to remain outstanding as the trial starts

• Having to collect, reconcile and store signed documents

• Storage and archiving costs for originals (25 years in Canada, EU...)

What about Health Authority Inspections?

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• Compliance with SOPs

• Signature date vs. effective date vs. document date – what rules?

• Blank signature blocks

• Request for list of documents requiring wet ink signatures

• Why were so many NTFs signed when there was no requirement?

Commonly Reported Issues:

Areas for Improvement

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• Sign fewer documents!o Examine what you are signing and why

o Reduce number of signers, especially “FYI” signers

o More achievable in eTMF than paper

• Replace wet ink with eSignatureo Many challenges, especially for outside parties

• Collect less papero Again, review what you are collecting and why

o Consider leaving signed paper at the site unless there is a regulation requiring the sponsor to retain

• Keep filing system for paper originals simpleo Often just chronological

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Thank You!

Special thanks to Sharon Ames for arranging signature interviews

and assisting with the survey.

Kathie Clark

Vice President, Product Management

Wingspan Technology, Inc.

kclark@wingspan.com