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Proving Electronic Signature as a Valuable Asset: A Special Report for CROs Globally

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Introduction:

CROs intend to guarantee that the procedures and workflows they use in their electronic Trial Master Files (eTMF) adhere to regulatory requirements, leading to a robust system that will generate complete documentation and will endure a company’s audits. 

Previously, companies encountered plenty of challenges in managing trial master file content on paper or in document share systems. The efforts needed to find, manage, and collaborate on essential documents on time have led several companies to look for more efficient options. 

According to research, signatures are necessary in a couple of instances. Usually, this is simply a way to honor a long-standing practice, where signatures were the best way to ensure that someone was given ample time to examine important documents before they were finalized.

Electronic documents don’t require signatures in most instances, because of the detailed logs and audit trails that document management systems provide. Although having knowledge of regulative needs will help companies in making the right choices about which signatures are worth the effort, and which ones should be eliminated.

TMF documents that require a signature

ICH-GCP only uses the word “signed” concerning these TMF documents:

Agreements/Contracts
Protocols and amendments
Completed case report forms
Completed consent forms
And CRF correction signature sheet/signature log

The governing picture for eSignatures

FDA’s treatment for eSignatures is based on 21 CFR 11, with Subpart C consisting of the most pertinent details. Like many other topics, the CFR only creates a basic structure and is not regularly updated to reflect technological developments. One of the most recent and most valuable tools for understanding the FDA’s contemporary perspective on eSignatures is the guidance document from June 2017, “Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 11 – Questions and Answers”.

GCP signature requirements

Indeed, the requirements around signatures aren’t pertaining to the electronic system—as the FDA has made it clear in documents such as “Part 11, Electronic Records; Electronic Signatures—Scope and Application.” “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 verified).”

For every quote pertaining to a signature, the linked artifact name from the TMF Reference Model 2.0 is recognized to identify how to execute the requirement. Finally, notes provide information on how a signature is expected to be acquired and whether a signature within an eTMF would be possible. If a signature is most likely to be acquired in a Regulatory Electronic Document Management System (EDMS), Clinical Trial Management System (CTMS), or Electronic Data Capture (EDC) system, the details are noted.

A broad collection of clinical requirements is analyzed. Some files are required only for submissions associated with clinical trials and are not essentially needed in the TMF. These documents are given in the table below as not belonging to the TMF:

Table 1 GCP Signature Requirements Analysis

CITATION
EXTRACT OF RULE
TMF REFERENCE MODEL ARTIFACT NAME
NOTES
LIKELY SIGNATURE CATEGORY

50.23(d)(1) ICH 8.3.3
IRB must review and approve use of investigational drug without informed consent when informed consent is not feasible.
“IRB/IEC Approval”
An IRB would not normally have access to any form of eSignature.
Handwritten/ scanned

56.115(a)(1), 812.62,812.64, ICH 8.2.7, ICH 8.3.3
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)
“IRB/IEC Approval”
An IRB would not normally have access to any form of eSignature.
Handwritten/ scanned

50.27(a), 50.27(b)(1),ICH 1.28, ICH 4.8.8, ICH 8.3.12
SIGNED INFORMED CONSENT FORMS
Signed informed consents are not part of the TMF Reference Model.
External tools exist for eSignature of informed consents, but subject would not sign in eTMF.
Handwritten/ scanned or exported from an eInformed Consent system

50.27(b)(2)
Short form written consent document to be signed by witness and subject or representative.
“Informed Consent Form”
(Alternative to standard Informed Consent) External tools exist for eSignature but subject would not sign in eTMF.
Handwritten/ scanned or eInformed Consent

50.27(b)(2)
Written summary of elements of consent to be signed by witness and person obtaining consent and IRB to approve written summary.
“IRB/IEC Approval”
An IRB would not normally have access to any form of eSignature.
Handwritten/ scanned

50.27(b)(2)
Written summary of elements of consent to be signed by witness and person obtaining consent and IRB to approve written summary.
“IRB/IEC Approval”
An IRB would not normally have access to any form of eSignature.
Handwritten/ scanned

56.102(m), 56.108(a)(4),56.108(c), 56.109(a), ICH 8.3.3
IRB reviews and approves the clinical investigation and changes.
“IRB/IEC Approval”
An IRB would not normally have access to any form of eSignature.
Handwritten/ scanned

312.120(c)(3)
For foreign studies (outside US), research is approved by an independent review committee.
Not included in TMF reference model
Not part of the TMF
eSignature or Handwritten/ scanned signature, probably in regulatory EDMS

54.4(a)(1)
Financial Disclosure Form FDA 3454 shall be dated and signed by the chief financial officer or other responsible corporate representative.
“Financial Disclosure Form”
FDA form 3454 does not allow for eSignature.
Handwritten/ scanned, probably in regulatory EDMS

312.53(c)(1)
Investigator Statement (Form FDA-1572) to be signed by investigator.
“Form FDA 1572”
FDA form that has Adobe self-sign mechanism
Signature within FDA form or Handwritten/ scanned signature

312.23(a)(1) (ix), 314.50(a)(5),314.94(a)(1)
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.
Not included in TMF reference model
Not part of the TMF
eSignature within FDA form or Handwritten/ scanned signature, probably in regulatory EDMS

314.72(a)(2)
If ownership of NDA changes, new owner signs an application form.
Not included in TMF reference model
Not part of the TMF
eSignature or Handwritten/ scanned signature, probably in regulatory EDMS

314.23(b), 314.50(g)(1)
Written statement signed by the original submitter is required to authorize references to information submitted previously by a person other than the applicant.
Not included in TMF reference model
Not part of the TMF
eSignature or Handwritten/ scanned signature, probably in regulatory EDMS

312.30(a), 312.30(b) (2)(i)
Protocol amendments are approved by IRB.
“IRB/IEC Approval” artifact
An IRB would not normally have access to any form of eSignature.
Handwritten/ scanned

312.59 ICH 4.6.3
Sponsor may authorize alternative disposition of unused supplies.
Does not appear to have any authorization for destruction, only records/ certificates. Possibly Trial Master File Plan.
eSignature or Handwritten/ scanned signature in eTMF

312.59 ICH 4.6.3
Sponsor may authorize alternative disposition of unused supplies.
Does not appear to have any authorization for destruction, only records/ certificates. Possibly Trial Master File Plan.
eSignature or Handwritten/ scanned signature in eTMF

312.60(c) ICH 5.14.3
Person who ships drug may authorize in writing alternative disposition of unused supplies.
Does not appear to have any authorization for destruction, only records/ certificates. Possibly Trial Master File Plan.
eSignature or Handwritten/ scanned signature in eTMF

314.50(g)(3)
For foreign studies (outside US), research is approved by an independent review committee.
Not included in TMF reference model
Not part of the TMF
eSignature or Handwritten/ scanned signature, probably in regulatory EDMS

314.53(c) (2)(i), 314.53(c)(4)
Statement signed by applicant or patent owner that a given patent applies to the NDA.
Not included in TMF reference model
Not part of the TMF
eSignature or Handwritten/ scanned signature, probably in regulatory EDMS

314.200(d) (3) iv
Statement signed by person responsible for such submission that includes all required studies and information.
Not included in TMF reference model
Not part of the TMF
eSignature or Handwritten/ scanned signature, probably in regulatory EDMS

314.200(e)(2) iv
Statement signed by person responsible for such submission that all records have been searched and the submission is true and accurate.
Not included in TMF reference model
Not part of the TMF
eSignature or Handwritten/ scanned signature, probably in regulatory EDMS

314.420(b)
NDA, abbreviated NDA application, amendment, or supplement may incorporate by reference all or part of any drug master file if the holder authorizes the incorporation in writing.
Not included in TMF reference model
Not part of the TMF
eSignature or Handwritten/ scanned signature, probably in regulatory EDMS

(not an agency requirement)
To document that IB was sent and received.
“Acceptance of Investigator Brochure” (05.02.01)
eSignature or Handwritten/ scanned signature in eTMF

ICH 8.2.2
To document investigator and sponsor agreement to the protocol.
“Protocol Amendment Signature Page” (05.02.02)
eSignature or Handwritten/ scanned signature in eTMF

ICH 8.2.2
To document investigator and sponsor agreement to the protocol amendment.
“Protocol Amendment Signature Page” (05.02.03)
eSignature or Handwritten/ scanned signature in eTMF

ICH 8.2.2
To document investigator and sponsor agreement to the protocol amendment.
“Protocol Amendment Signature Page” (05.02.03)
eSignature or Handwritten/ scanned signature in eTMF

ICH 4.1.5, ICH 8.3.24 But does not dictate signature
To document delegation by the Principal Investigator of trial specific tasks to site personnel conducting the trial.
“Site Signature Sheet” (05.02.19) Aka “Delegation of Authority, Site Responsibility Log”
eSignature or Handwritten/ scanned signature in eTMF

Not an agency requirement
Various plans, procedures, etc. that do not require signature per GCP but may be signed per the sponsor’s practice
Various
eSignature or Handwritten/ scanned signature in eTMF

ICH 8.3.24
To document signatures and initials of all persons authorised to make entries and/or corrections on CRFs
Presumably “Site Signature Sheet” (05.02.19) although definition does not match
Handwritten/ scanned as the purpose is to document signatures

ICH 7.5
Signature page for Investigator’s Brochure (optional)
“Investigator Brochure” (02.01.01)
eSignature or Handwritten/ scanned signature in eTMF; might be signed in regulatory EDMS

ICH 1.17, 8.2.6, 812.43(c)
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 financial 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)
“Site Contact Details“ (05.01.01) “Clinical Study Agreement, Investigator Financial Agreement, Investigator Contract” (05.02.12) “Contractual Agreement” (09.02.03)
Does not specify which signatures are required Highly unlikely to be signed in the eTMF
Handwritten/ scanned or possibly eSignature in a contract management system.

ICH 8.2.2
SIGNED PROTOCOL AND AMENDMENTS, IF ANY, AND SAMPLE CASE REPORT FORM (CRF)
“Protocol” (02.01.02) “Protocol Amendment” (02.01.04) “Sample Case Report Form” (02.01.07)
Note: Does not specify which signatures are required – or that any signatures are required for sample CRF
eSignature or Handwritten/ scanned signature, probably in regulatory EDMS or CTMS

ICH 8.3.14
SIGNED, DATED AND COMPLETED CASE REPORT FORMS (CRF)
CRFs are not part of the TMF Reference model
Changes to CRFs would not be created in the eTMF; final copies might possibly be stored in the eTMF
eSignature or Handwritten/ scanned signature within an Electronic Data Capture (EDC) system.

Requirement of signatures from a diverse set of sources and collaborators

Clinical researchers, statisticians, data supervisors, and clinical executives sign investigator brochures, protocols, and records, typically in a regulatory EDMS.
Investigators and sub-investigators sign FDA 1572s, and investigators accept invoices of protocol modifications and investigator brochure updates.
IRB/IEC members sign various approval forms and acknowledgments based on their documented operating procedures. 
Various website personnel sign CRFs (often within an ED system) and signature logs. 
Informed consent agreements are signed by subjects on paper or in an eInformed consent system.
Personnel from the sponsor, CRF, investigator/institution, laboratories, etc., sign agreements on paper or within a contract management system.
The Financial Disclosure Form FDA 3454 is signed by the chief financial officer or other responsible corporate representatives.

Table 2 – How Documents are Signed

TYPE OF SIGNATURE
DEFINITION
ACCEPTABILITY
PORTABILITY

Handwritten
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.
Handwritten signatures are accepted by all health authorities.
Handwritten signatures can be verified 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 certified copy (a copy of original information that has been verified, as indicated by dated signature, as an exact copy having all of the same attributes and information as the original).

Electronic – Non Digital
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.
Electronic signatures are accepted by the FDA as long as the regulations defined in 21 CFR Part 11 are met. Other authorities have not generally established a position.
The validity of signatures and integrity of the document can be verified inside the system where the signature was applied, but not outside of the system.

Electronic – Digital
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 verified.
Digital signatures are accepted by the FDA as long as the regulations defined in 21 CFR Part 11 are met. Other authorities have issues specific rules on the acceptability of digital signatures.
The validity of signatures and integrity of the document can be verified. Verification of the identity of the signer requires access to a trusted third party who can validate the signer.

The burden of handwritten signatures

Several files originate from other electronic systems and are obtained as final. Consequently, the signature system selected for those files has already been chosen before entering the eTMF. 
A regular TMF still includes much-scanned content signed on paper.
A significant variety of signers do not have access to the eTMF to participate in the process and electronic signature. Additionally, even if these signers could be granted access, there will be a significant resulting burden on its IT team to sustain a stable stream of incoming and outgoing investigators, partners, and IRB/IEC members

Advancing towards a digital future

Moving from paper to an electronic TMF brings significant challenges where all the documents are signed electronically. Therefore, several sponsors and CROs depend greatly on scanned content for TMFs. This enforces the burden of maintaining paper files, which continue to be the official records for a trial unless a comprehensive process is implemented for certifying duplicates to enable the destruction of paper originals.

The resulting expenses and delays are those related to couriering files for signature, archiving paper files, and ensuring they are retrievable for their required retention periods, particularly in case of an audit. 

A complete shift to electronic documents and signatures might not be practical right now, but incremental steps can minimize the burden. There can be various possibilities, including minimizing signatures to those required by authorities, offering extra collaborators access to the eTMF, or executing a system that enables signatures outside the eTMF. 

Although eTMF access can be extended to investigators and other site staff, IRBs and IECs, and other third parties, the influence needs to be meticulously taken into consideration. Some software systems depend on a per-user licensing model that may lead to primary and recurring expenses or require components or access mechanisms that third-party users may lack. Additionally, handling accounts and verifying digital identifications for frequently changing third-party users can be a vast IT burden unless a more lightweight strategy to account provisioning that still guarantees the credibility of individuals can be executed. 

Electronic signatures for clinical trials

We understand that CROs across the globe are going paperless, and electronic signatures and record-keeping are becoming increasingly acceptable. So, the question arises, how does the clinical research industry benefit from this? It would be unfair to exclude the other players in a clinical trial ecosystem like IRBs/ IECs, sponsors, site personnel, and investigators who could gain from this concept.

Costs and time restrictions are frequently on a surge for sponsors and CROs. They are required to keep including cutting-edge techniques to curb both. As a result, corporates are adapting to approaches like electronic signatures and digital record keeping in clinical trials to execute research procedures electronically. Electronic signatures allow all the key players in clinical trials to submit their documents electronically. This, in turn, makes way for effective regulatory compliance by saving a considerable amount of time and saving many expenses too.

Besides this, other benefits of electronic signatures in clinical trials are that it offers concrete and compliant evidence of the signer’s identity and therefore offer integrity for anybody who receives the document. It paves the way for a concrete audit trail that enables the restoration of events associated with the document’s creation, modification, and deletion. It is often easy to manipulate and encourage malpractices with conventional handwritten signatures, but this is impossible with electronic signatures.