SIGNATURE REQUIREMENTS FOR THE eTMF:

White Paper

SIGNATURE REQUIREMENTS FOR

THE eTMF:

A Regulatory and Technological Assessment

KATHIE CLARK, Senior Director - Oering Management, Orchestrated Content Management

TABLE OF CONTENTS

Overview 3

Signatures Required by Good Clinical Practices 4

Table 1 - GCP Signature Requirements Analysis 5

How are Signatures Obtained 9

Table 2 - How Documents are Signed 10

The Signature Burden 11

Moving Towards a Digital Future 11

Summary 15

Signature Requirements for the eTMF iqvia.com | 3

OVERVIEW

While working with our clients, we at IQVIA often participate in discussions around which documents in an electronic

Trial Master File (eTMF) really require signatures. To provide a solid basis for decision-making, we’ve researched both

the regulatory basis for signatures and the technology implications around how to collect signatures.

Research shows that relatively few documents have signature requirements based on regulations.

Often, signatures are obtained because of an organizational policy, written or unwritten, not based on regulations.

The UK Medicines and Healthcare Products Regulatory Agency (MHRA) reinforces this distinction in its 2012 Good

Clinical Practices Guide:

Often, obtaining signatures is a holdover from the paper world where signatures were the only way to prove that

an individual had an opportunity to review a document before it was nalized. Since modern electronic document

management systems provide this information in logs and audit trails, the record exists without the need for

signatures.

Knowing the actual regulatory requirements will assist organizations in making sound decisions about which

signatures add value, and eliminating signatures they deem unnecessary.

Sponsors and CROs want to ensure that the processes and workows they use in

their electronic Trial Master Files (TMF) comply with all regulatory requirements,

resulting in a robust system that will produce complete documentation able to

withstand an agency audit.

“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).”

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Of course, the requirements around signatures aren’t actually related to the electronic system – as the FDA has made

clear in documents such as “Part 11, Electronic Records; Electronic Signatures — Scope and Application”, which states

that 21 CFR Part 11 applies to:

• The International Conference on Harmonisation (ICH) documents GCP in “Guideline for Good Clinical

Practice E6 (R1)”.

• The US Food and Drug Administration (FDA) considers ICH GCP only a recommendation, and does

not codify GCP in a single set of regulations. Instead, regulations are scattered through the Code of

Federal Regulations (CFR) as documented on the FDA’s web page “FDA Regulations Relating to Good

Clinical Practice and Clinical Trials”.

Signature requirements for TMF documents are established in several predicate rules related to Good

Clinical Practice (GCP), and are the same for paper and electronic documents.

The following table provides an analysis of requirements for signature appearing in predicate rules. A very

conservative position was used; that is, any reference to approvals, initials, authorizations, etc. was interpreted as a

potential signature requirement.

For each citation related to a signature, the associated artifact name from the Trial Master (TMF) Reference Model

2.0 is identied to assist in determining how to implement the requirement. Finally, notes provide details on how a

signature is likely to be obtained and whether signature within an eTMF would be feasible. If a signature is more likely

to be obtained in a Regulatory Electronic Document Management System (EDMS), Clinical Trials Management System

(CTMS), or Electronic Data Capture (EDC) system, the specics are noted.

A broad set of clinical requirements is examined. Some documents are needed only for submissions related to clinical

trials and are not actually required in the TMF. These documents are noted in the table as not being part of the TMF.

SIGNATURES REQUIRED BY GOOD CLINICAL PRACTICES

“Electronic signatures that are intended to be the equivalent of handwritten signatures, initials, and

other general signings required by predicate rules. Part 11 signatures include electronic signatures

that are used, for example, to document the fact that certain events or actions occurred in accordance

with the predicate rule (e.g. approved, reviewed, and veried).”

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Table 1 GCP Signature Requirements Analysis

Citation

Notes

Likely Signature

Category

Extract of Rule

TMF Reference

Model Artifact Name

IRB must review

and approve use of

investigational drug

without informed consent

when informed consent is

not feasible.

SIGNED INFORMED

CONSENT FORMS

Written summary of

elements of consent to

be signed by witness and

person obtaining consent

and IRB to approve

written summary.

Short form written consent

document to be signed

by witness and subject or

representative.

IRB reviews and approves

the clinical investigation

and changes.

DATED, DOCUMENTED

APPROVAL/

FAVOURABLE OPINION

OF INSTITUTIONAL

REVIEW BOARD (IRB) /

INDEPENDENT ETHICS

COMMITTEE (IEC) OF THE

FOLLOWING:

• protocol amendment(s)

• revision(s) of:

• informed consent form

• any other written

information to be

provided to the subject

• advertisement for

subject recruitment

(if used)

• any other documents

given approval/

favourable opinion

• continuing review of

trial (where required)

An IRB would not normally

have access to any form of

eSignature.

External tools exist for

eSignature of informed

consents, but subject would

not sign in eTMF.

An IRB would not normally

have access to any form of

eSignature.

An IRB would not normally

have access to any form of

eSignature.

(Alternative to standard

Informed Consent) External

tools exist for eSignature

but subject would not sign

in eTMF.

An IRB would not normally

have access to any form of

eSignature.

An IRB would not normally

have access to any form of

eSignature.

“IRB/IEC Approval”

Signed informed

consents are not part

of the TMF Reference

Model.

“IRB/IEC Approval”

“Informed Consent

Form”

“IRB/IEC Approval”

Handwritten/ scanned

or exported from an

eInformed Consent system

Handwritten/ scanned

Handwritten/ scanned or

eInformed Consent

Handwritten/ scanned

50.23(d)(1)

ICH 8.3.3

50.27(a),

50.27(b)(1),

ICH 1.28, ICH

4.8.8, ICH

8.3.12

50.27(b)(2)

56.102(m),

56.108(a)(4),

56.108(c),

56.109(a),

ICH 8.3.3

56.115(a)(1),

812.62,

812.64,

ICH 8. 2 .7,

ICH 8.3.3

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Table 1 GCP Signature Requirements Analysis

Citation

Notes

Likely Signature

Category

Extract of Rule

TMF Reference

Model Artifact Name

For foreign studies

(outside US), research

is approved by an

independent review

committee.

Investigator Statement

(Form FDA-1572) to be

signed by investigator.

If ownership of NDA

changes, new owner

signs an application

form.

Protocol amendments

are approved by IRB.

Person who ships drug

may authorize in writing

alternative disposition of

unused supplies.

IND cover sheet, NDA

and Abbreviated

NDA application

forms require

signature of sponsor.

Countersignature of

US-based representative

also required if sponsor

has no US base.

Written statement

signed by the original

submitter is required to

authorize references to

information submitted

previously by a person

other than the applicant.

Sponsor may authorize

alternative disposition

of unused supplies.

Financial Disclosure Form

FDA 3454 shall be dated

and signed by the chief

nancial ocer or other

responsible corporate

representative.

Not part of the TMF

FDA form that has Adobe

self-sign mechanism

Not part of the TMF

An IRB would not normally

have access to any form of

eSignature.

Not part of the TMF

FDA form 3454 does not

allow for eSignature.

Not included in TMF

reference model

“Form FDA 1572”

Not included in TMF

reference model

“IRB/IEC Approval”

artifact

Not included in TMF

reference model

Not included in TMF

reference model

Does not appear to have

any authorization for

destruction, only records/

certicates. Possibly Trial

Master File Plan.

Does not appear to have

any authorization for

destruction, only records/

certicates. Possibly Trial

Master File Plan.

“Financial Disclosure

Form”

eSignature or

Handwritten/ scanned

signature, probably in

regulatory EDMS

Signature within FDA form

or Handwritten/ scanned

signature

eSignature within FDA

form or Handwritten/

scanned signature,

probably in regulatory

EDMS

Handwritten/ scanned

eSignature or

Handwritten/ scanned

signature in eTMF

eSignature within FDA form

or Handwritten/ scanned

signature, probably in

regulatory EDMS

eSignature or

Handwritten/ scanned

signature, probably in

regulatory EDMS

eSignature or

Handwritten/ scanned

signature in eTMF

Handwritten/ scanned,

probably in regulatory

EDMS

312.120(c)(3)

312.53(c)(1)

314.72(a)(2)

312.30(a),

312.30(b)

(2)(i)

312.60(c)

ICH 5.14.3

312.23(a)(1)

(ix),

314.50(a)(5),

314.94(a)(1)

314.23(b),

314.50(g)(1)

312.59

ICH 4.6.3

54.4(a)(1)

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Table 1 GCP Signature Requirements Analysis

Citation

Notes

Likely Signature

Category

Extract of Rule

TMF Reference

Model Artifact Name

For foreign studies

(outside US), research

is approved by an

independent review

committee.

Statement signed by

person responsible for such

submission that includes

all required studies and

information.

NDA, abbreviated NDA

application, amendment,

or supplement may

incorporate by reference all

or part of any drug master

le if the holder authorizes

the incorporation in writing.

To document investigator

and sponsor agreement to

the protocol.

To document

delegation by the

Principal Investigator

of trial specic tasks

to site personnel

conducting the trial.

Statement signed by

applicant or patent owner

that a given patent applies

to the NDA.

Statement signed by

person responsible

for such submission

that all records have

been searched and

the submission is true

and accurate.

To document that

IB was sent and

received.

To document

investigator and

sponsor agreement

to the protocol

amendment.

Not part of the TMF

Not included in TMF

reference model

Not included in TMF

reference model

Not included in TMF

reference model

“Protocol Amendment

Signature Page”

(05.02.02)

“Site Signature Sheet”

(05.02.19)

Aka “Delegation

of Authority, Site

Responsibility Log”

Not included in TMF

reference model

Not included in TMF

reference model

“Acceptance of

Investigator Brochure”

(05.02.01)

“Protocol Amendment

Signature Page”

(05.02.03)

eSignature or

Handwritten/ scanned

signature, probably in

regulatory EDMS

eSignature or

Handwritten/ scanned

signature, probably in

regulatory EDMS

eSignature or

Handwritten/ scanned

signature, probably in

regulatory EDMS

eSignature or

Handwritten/ scanned

signature in eTMF

eSignature or

Handwritten/ scanned

signature in eTMF

eSignature or

Handwritten/ scanned

signature, probably in

regulatory EDMS

eSignature or

Handwritten/ scanned

signature, probably in

regulatory EDMS

eSignature or

Handwritten/ scanned

signature in eTMF

eSignature or

Handwritten/ scanned

signature in eTMF

314.50(g)(3)

314.200(d)

(3) iv

314.420(b)

ICH 8.2.2

ICH 4.1.5,

ICH 8.3.24

But does

not dictate

signature

314.53(c)

(2)(i),

314.53(c)(4)

314.200(e)

(2) iv

(not an

agency

requirement)

ICH 8.2.2

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Table 1 GCP Signature Requirements Analysis

Citation

Notes

Likely Signature

Category

Extract of Rule

TMF Reference

Model Artifact Name

Various plans, procedures,

etc. that do not require

signature per GCP but

may be signed per the

sponsor’s practice

Signature page for

Investigator’s Brochure

(optional)

SIGNED PROTOCOL

AND AMENDMENTS, IF

ANY, AND SAMPLE CASE

REPORT FORM (CRF)

To document signatures

and initials of all persons

authorised to make

entries and/or corrections

on CRFs

SIGNED, DATED AND

COMPLETED CASE REPORT

FORMS (CRF)

Contracts

A written, dated, and

signed agreement

between two or more

involved parties that sets

out any arrangements

on delegation and

distribution of tasks

and obligations and, if

appropriate, on nancial

matters. The protocol may

serve as the basis of a

contract.

SIGNED AGREEMENT

BETWEEN INVOLVED

PARTIES, e.g.:

• investigator/institution

and sponsor

• investigator/institution

and CRO

• sponsor and CRO

• investigator/institution

and authority(ies)

(where required)

Various

“Investigator Brochure”

(02.01.01)

“Protocol” (02.01.02)

“Protocol Amendment”

(02.01.04)

“Sample Case Report

Form” (02.01.07)

Presumably “Site Signature

Sheet” (05.02.19) although

denition does not match

CRFs are not part of the

TMF Reference model

“Site Contact Details“

(05.01.01)

“Clinical Study Agreement,

Investigator Financial

Agreement, Investigator

Contract” (05.02.12)

“Contractual Agreement”

(09.02.03)

eSignature or

Handwritten/ scanned

signature in eTMF

eSignature or

Handwritten/ scanned

signature in eTMF; might

be signed in regulatory

EDMS

eSignature or

Handwritten/ scanned

signature, probably in

regulatory EDMS or CTMS

Handwritten/ scanned

as the purpose is to

document signatures

eSignature or

Handwritten/ scanned

signature within an

Electronic Data Capture

(EDC) system.

Handwritten/ scanned

or possibly eSignature in

a contract management

system.

Not an

agency

requirement

ICH 7.5

ICH 8.2.2

ICH 8.3.24

ICH 8.3.14

ICH 1.17,

8.2.6,

812.43(c)

Does not specify which

signatures are required

Highly unlikely to be signed

in the eTMF

Note: Does not specify which

signatures are required –

or that any signatures are

required for sample CRF

Changes to CRFs would not

be created in the eTMF; nal

copies might possibly be

stored in the eTMF

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Although the documents requiring signature by GCP are not numerous, signatures are needed from a diverse set of

collaborators and sources.

Many of these collaborators will not have access to the eTMF. As a result, their signatures must be applied externally.

HOW ARE SIGNATURES OBTAINED?

• Clinical scientists, statisticians, data

managers and clinical executives sign

investigator brochures, protocols and

reports, usually in a regulatory EDMS

• For documents originating in other

electronic systems, the signature

mechanisms available in those systems

will be used and normally a copy of the

signed document made available in the

eTMF. For example, a protocol might

be authored, reviewed and signed in

a regulatory EDMS and a nal PDF copy

uploaded to an eTMF.

• For documents created electronically on a le system, signatures may be obtained electronically if a mechanism

is available to the signer. For example, an FDA 1572 Statement of Investigator form can be lled out within

Adobe and signed using an available digital certicate outside of any document management system. However,

it is still more common that these documents are printed, signed and scanned.

It’s also worthwhile to consider the impact of how the documents are signed. The signature mechanism that is used may

impact the willingness of sponsors or regulatory authorities to trust that the signatures are valid.

• Investigators and sub-investigators sign

FDA 1572s and investigators acknowledge

receipt of protocol amendments and

Investigator Brochure updates

• IRB/IEC members sign a number of

approval forms and acknowledgements

in accordance with their documented

operating procedures

• Subjects sign informed consent

agreements, on paper or in an eInformed

Consent system

• Personnel from the sponsor, CRF,

investigator/institution, labs, etc. sign

contracts, on paper or within a contract

management system

• The chief nancial ocer or other responsible corporate representative signs the Financial Disclosure

Form FDA 3454

• Various site personnel sign CRFs

(sometimes within an EDC system) and

signature logs

• For documents completed on paper, signatures

are generally handwritten and the signed

document scanned to PDF format and released

or imported into the eTMF as needed. Some

documents may never be scanned – for example,

signed informed consent forms are not required

as part of the sponsor’s les and need not be

imported to an eTMF.

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Table 2 - How Documents are Signed

Type of

Signature

PortabilityDenition

Acceptability

Signature executed using a pen,

including signatures captured

on a capture pad using a stylus

unless biometric characteristics

are captured in order to qualify

as an electronic signature.

Electronic signature based

upon cryptographic methods

of originator authentication,

computed by using a set of rules

and a set of parameters such that

the identity of the signer and the

integrity of the data can be veried.

Computer data compilation

of any symbol or series of

symbols executed, adopted,

or authorized by an individual

to be the legally binding

equivalent of the individual’s

handwritten signature.

Handwritten signatures

are accepted by all health

authorities.

Digital signatures are accepted

by the FDA as long as the

regulations dened in 21

CFR Part 11 are met. Other

authorities have issues specic

rules on the acceptability of

digital signatures.

Electronic signatures are

accepted by the FDA as long

as the regulations dened in

21 CFR Part 11 are met. Other

authorities have not generally

established a position.

Handwritten

Electronic -

Digital

Electronic –

Non Digital

Handwritten signatures can be

veried only by comparison with

signature logs or records such as

those required by GCP. It is not

possible to verify the integrity of a

document signed with a handwritten

signature except by comparing it to

a paper original or a certied copy

(a copy of original information that

has been veried, as indicated by

dated signature, as an exact copy

having all of the same attributes and

information as the original).

The validity of signatures and

integrity of the document can be

veried. Verication of the identity

of the signer requires access to a

trusted third party who can validate

the signer.

The validity of signatures and

integrity of the document can be

veried inside the system where

the signature was applied, but not

outside of the system.

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Moving away from handwritten signatures is a goal of many electronic document management systems. However, it’s

particularly challenging in an eTMF system.

THE SIGNATURE BURDEN

• Many documents originate in other

electronic systems and are received as

nal. As a result, the signature mechanism

chosen for these documents has already

been decided before they enter the eTMF.

• A signicant number of signers do not have access to the eTMF to participate in workow and electronic

signature. Furthermore, even if these signers could be granted access, the resulting burden on a

company’s IT sta would be signicant in order to support a steady stream of incoming and outgoing

investigators, partners and IRB/IEC members.

• A typical TMF still consists of a good deal of

scanned content signed on paper.

Substantial obstacles exist in moving away from paper

to a eTMF where all documents originate electronically

and are signed digitally. As a result, many sponsors

and CROs continue to rely heavily on scanned content

for TMFs. This imposes the burden of maintaining

paper documents, which remain the ocial records for

a trial unless an extensive process is put in place for

certifying copies in order to allow the destruction of

paper originals. Resulting costs and delays include those

associated with couriering documents for signature,

archiving paper documents, and ensuring they are

retrievable for their required retention periods and

especially in case of an audit.

While a total shift to electronic documents and

signatures may not be realistic at this time, incremental

steps can reduce the burden. Possibilities include

reducing signatures to those required by authorities,

providing additional collaborators with access to the

eTMF or implementing a system that allows signatures

outside the eTMF.

Although eTMF access can be expanded to investigators

and other site sta, IRBs and IECs, and other third

parties, the impact must be carefully considered. Some

software systems rely on a per-user licensing model

that may result in signicant initial and ongoing costs,

or may require components or access mechanisms that

third party users may not have. In addition, managing

accounts and conrming digital identities for constantly

changing third party users can become a sizable IT

burden unless a more lightweight approach to account

provisioning that still ensures validity of users can be

implemented. On the positive side, providing eTMF

access results in a number of benets around processes

and notications beyond obtaining signatures.

Likewise, implementing an external system for

applying digital signatures sounds attractive but has

its own set of issues. 21 CFR Part 11 requirements

must be maintained, which eliminates a number of

commercial solutions from being used o the shelf. The

establishment and maintenance of digital identities is a

major consideration.

Moving Towards a Digital Future

Signature Requirements for the eTMF iqvia.com | 12

SUMMARY

A signicant number of signers do not have access to the eTMF to participate in workow and electronic signature.

Furthermore, even if these signers could be granted access, the resulting burden on a company’s IT sta would

be signicant in order to support a steady stream of incoming and outgoing investigators, partners and IRB/IEC

members.

• A discussion of signatures needed and how they will be gathered

• An evaluation of whether copies will be certied to allow the elimination of paper

• An assessment of which collaborators will access the system directly

• An assessment of how the system will withstand an audit by a health authority accessing it directly

or through inspection of records

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