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To protect human subjects in clinical research, the U.S. Food and Drug Administration (FDA) maintains and enforces specific regulations. Research stakeholders must track, document, and store the required information for trial oversight and monitoring to comply with regulations.
This blog identifies applicable regulations and outlines regulated documents and data in clinical research and the systems used by sponsors, contract research organizations (CROs), monitors, and research sites to collect, exchange, and store them.
Introduction to Required Research Documents and Regulatory Compliance
There are three primary regulations impacting trial documentation:
- ICH Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting for trials involving the participation of human subjects. In short, GCP dictates what data and documents need to be collected, stored, and audit-ready.
- FDA 21 CFR Part 312 describes specific roles, responsibilities, and documentation requirements for investigational new drugs (INDs).
- FDA 21 CFR Part 11 (commonly known as Part 11) “applies to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted.” Since many clinical research teams leverage electronic systems to manage clinical trials, ensuring compliance with 21 CFR Part 11 is essential.
Additional Resource: Regulatory Fine Points: What Sites Need to Do for Part 11 Compliance
What is an Electronic Master File (eTMF)?
An electronic trial master file (eTMF) is a technology solution designed to organize, collect, store, track, and archive required and essential study documents. The eTMF is an electronic version of the trial master file (TMF) that is now industry standard. Historically, the TMF was organized in paper form.
The TMF is the collection of required documents associated with a single clinical trial that demonstrate the trial’s compliant conduct and all associated activities for evaluation by regulators. If you think of the clinical trial process as a journey, with a start and a finish, each step along the way must be captured and updated in a central location: the TMF.
According to FDA and international GCP guidelines, TMFs are required for every study but are not required to be electronic. By regulation, sponsors are responsible for the maintenance, accessibility, and accuracy of the TMF. If a sponsor chooses to utilize an eTMF, they are responsible for ensuring the system is secure and 21 CFR Part 11 validated.
What Documents are Collected and Stored in an eTMF?
GCP guidelines dictate which documents need to be included and categorized in the eTMF. For example:
- Essential study documents:
- protocol, protocol amendments, investigator’s brochure, procedures and manuals, visit guidance, etc.
- Training documentation and materials:
- certificates, videos, supporting content, etc.
- Funding documentation:
- contracts, budgets, negotiations, etc.
- Safety documentation:
- safety letters, serious adverse event (SAE) reports, etc.
- Ethics committee’s documents:
- protocol amendments, approvals, communication, etc.
- Audit or monitoring documents:
- onsite visit records, audit findings, etc.
- Participant information:
- informed consent forms, visit guidance, brochures, recruitment materials, patient diaries, etc.
- Site-specific documents:
- site CVs, training documentation, site standard operating procedures (SOPs), etc.
What Systems Integrate with an eTMF?
Most of the documents required for collection and storage within an eTMF originate outside of sponsor systems. If a research site stores study documents in an electronic investigator site file (eISF), those documents would need to be routed to the corresponding eTMF.
Software and platforms such as an electronic IRB (eIRB) system, eRegulatory (eReg) management system, e-mail programs, and clinical trial management systems (CTMS) can integrate with an eTMF. Integrating systems reduces the amount of work needed to manually move documents from one system to another, and it also reduces the risk of mistakes.
What is an Electronic Investigator Site File (eISF)?
An electronic investigator site file (eISF) is a technology solution designed to organize, collect, store, track, and archive required and essential study documents for an individual site involved in a particular research study. The eISF is an electronic version of the ISF, which was historically organized in paper form. The eISF at an individual research site works together with the sponsor’s eTMF, which collects and stores data associated with each research site involved in the clinical trial. A research site is also responsible for storing and archiving their ISF.
Additional Resource: 12 Items Auditors Look for When Reviewing an Investigator Site File
What Documents are in an eISF?
Like an eTMF, an eISF collects and stores clinical research regulatory documents, but only related to a particular research site. For example:
- Essential study documents:
- protocol, protocol amendments, investigator’s brochure, procedures and manuals, visit guidance, etc.
- Site-specific documents:
- site CVs, training documentation, site SOPs, etc.
- Site-specific participant recruitment and engagement information:
- informed consent forms, visit guidance, brochures, recruitment materials, patient diaries, etc.
- Site-specific monitoring or audit records
What is the Difference Between an eTMF and eISF?
An eISF is a subset of documents required to be collected and stored in an eTMF. An eISF is compiled by an individual research site, while all eISF documents within the eTMF are collected and compiled by the research sponsor.
How Long Must Essential Clinical Research Documents be Archived for?
The records in both an eISF and eTMF for each clinical trial must be stored and accessible for 30 years after a study closes. Regulators, monitors, and other auditors may access the documents over time to review trial conduct and data.
What is Secure Document Exchange?
Secure document exchange describes the workflow for exchanging regulated research documents between research stakeholders. Secure document exchange can help reduce administrative burden, improve data accuracy and security, and automate document collection and updating.
Most document exchange activities happen during the study startup process of a clinical trial. To start a clinical trial, sponsors, CROs, and research sites need to work together to make sure everyone is ready to do the research and meets all the regulatory requirements. Historically, these processes have been burdensome to both sites and sponsors due to lack of communication between technology systems.
Advarra enables efficient and compliant document management for both sites and sponsors. Secure document exchange between Advarra’s eReg and Longboat Platform provides end-to-end integration for automated, seamless exchange of research documents between sites, sponsors, and CROs.
Author: Stuart Cotter, Vice President of Product Management, Advarra
