Clinical trial documentation: eISF v eTMF - what's the difference?

In clinical trial management two sets of documents are essential to success: the Trial Master File (TMF) and the Investigator Site File (ISF). But what’s the difference between the two and who is responsible for each?

Though often mentioned in the same breath and frequently conflated (even in the minds of those planning these files for inspection), the TMF and the ISF are usually created and maintained by different organisations in the value chain.  

So what exactly are they for and what goes into each?

And how can investigators best create and maintain the documentation they are responsible for?

What is a TMF (Trial Master File)?

The Trial Master File (TMF) is a centralised collection of essential documents that are typically curated and maintained by the sponsor or a Contract Research Organisation (CRO). This compilation tells the complete story of a clinical trial, from its design through to its execution and closeout.

The TMF exists to demonstrate that the trial was conducted in compliance with Good Clinical Practice (GCP) guidelines issued by the International Council for Harmonisation (ICH) - as well as regulatory requirements from authorities such as the FDA, EMA, and MHRA.

TMF Overview:

• Owner: Trial sponsor or Contract Research Organisation (CRO)
• Scope: Global — spanning the entire clinical trial lifecycle
• Purpose: Oversight, governance, and regulatory inspection readiness

Key TMF Documents Include:

• Clinical trial protocols and amendments
• Ethics committee correspondence
• Site qualification and initiation reports
• Monitoring visit logs
• Regulatory submissions and approvals

A well-maintained TMF allows regulators to reconstruct the history of the trial without ambiguity - it is the backbone of trial transparency and accountability.

What is an ISF (Investigator Site File)?

The Investigator Site File (ISF) is the site-level counterpart to the TMF. Managed by the Principal Investigator (PI) and their team, it contains the essential documents required to demonstrate that the site has conducted the trial ethically and in line with Good Clinical Practice (GCP).

Importantly, while the term ISF is widely used across the clinical research industry, it’s not officially recognised by regulators like the FDA, EMA, or ICH. Instead, GCP guidelines refer more broadly to the investigator’s obligation to maintain essential documents. In practice, these documents are what clinical teams commonly refer to as the ISF — or, historically, the regulatory binder.

ISF Overview:

• Owner: Principal Investigator or site research team
• Scope: Local, site-specific documentation
• Purpose: To demonstrate site-level compliance and ethical trial conduct

Key ISF Documents Include:

• Signed informed consent forms
• Delegation of duties logs and staff training records
• Site-specific ethics approvals
• Drug/device accountability logs
• Subject enrolment and screening logs

Because the ISF is likely to include subject-identifying information, such as signed consent forms and screening logs, it must remain secure and accessible only to authorised site personnel. These privacy obligations are a key reason why the ISF and TMF, while overlapping, must remain separate.

Regulatory inspectors from the MHRA, FDA, or EMA will typically begin their audit at the ISF — making it your first line of regulatory scrutiny.

TMF vs. ISF: At-a-Glance

For a full list of the documents that need to be created and maintained by primary investigators and sponsors - you can refer to section 8 of the ICH E6 (R2).  

How do they work together?

The ISF is not just a standalone folder — it’s the source for many documents that also end up in the TMF. But while the site collects and manages the ISF, the sponsor assembles the full TMF, drawing in appropriate, non-identifiable content from each participating site.

This dual responsibility requires clear processes and airtight documentation workflows on both sides.

The shift to digital ISFs

The other name for the ISF, the regulatory binder, reminds us that the ISF has historically been a manually collated batch of physical documents. But the burden of curating such a large collection of paper-based files in an increasingly paperless world is obvious:

“In the clinical trial world, if it isn't documented, it didn't happen. In a paper-based system, you have to keep every single piece of paper - every email that comes in has to be printed. Our Trial Master Files were typically 50 or more lever arch files long."

Julie Errington, Clinical Trials Analyst/Coordinator, NCCPG

As trials become more complex and remote oversight becomes a standard requirement, many sites are now looking to digtitise their IMFs to stay on top of compliance while streamlining their day-to-day operations.

Digitising ISFs allow sites to:

• Ensure real-time completeness and traceability for all required documentation
• Enable remote sponsor or CRO access for monitoring
• Enable digital auditing
• Minimise risks of document loss, delay, or misplacement from paper-based systems

But what digital tools do investigators need to ensure they keep their systems compliant?

Why you can’t rely on Dropdox or Google Drive

Many research teams try to stitch together their digital ISF using tools like Dropbox, Google Drive, or SharePoint.

But while these platforms seem familiar, easy to set up, and more cost-effective than a proprietary software, they can be hard to when it comes to clinical trial compliance:

• Lack of secure electronic signature and record controls: DIY systems often can't meet the rigorous requirements of FDA 21 CFR Part 11, particularly around electronic records and signatures. They typically lack built-in compliance features like system validation, audit trails, and verifiable electronic signatures. Compliant systems ensuire user authentication before signing - and links signatures securely and permanently to their respective records — without this, sites risk regulatory findings casting doubt on their process.
• Inadequate version control and audit trails: Without automated audit logs and secure version histories, it’s difficult to demonstrate document authenticity — a key expectation under ALCOA++ principles.
• Manual oversight requirements: They lack pre-configured workflows for document review, approval, and expiry management, increasing administrative burden and the risk of human error.

When subject safety, data integrity, and trial credibility are on the line, relying on generic cloud storage isn't enough. Only a purpose-built, validated eISF can ensure your site maintains full regulatory compliance — and inspection readiness — at every stage of the trial.

Why most eTMF platforms don’t work for investigator sites

But eTMF solutions like Veeva Vault or Medidata Rave are largely built for sponsors. While they’re typically robust and compliant with GCP, they can also come with heavy overheads and prove:

• Too expensive for smaller, university based teams
• Over-engineered for primary investigator needs
• Difficult to configure and right size to your needs
• Too inflexible, with rigid workflows that can’t be modified to reflect the reality of site operations

Even so, sponsors and CROs are increasingly looking for investigating teams that can give them the data they need for their eTFM in the digital format they require.

Luckily, there is another way to manage your ISF

Investigators looking to digitise their site files without taking on the complexity, rigidity, or cost of sponsor-focused eTMF systems should look for flexible document control software that can be easily adapted to manage an Investigator Site File (ISF) — without compromising on compliance.

The right platforms can offer:

• Built-in compliance with FDA 21 CFR Part 11, EU Annex 11, and ICH GCP requirements.
• Flexible, site-driven workflows that reflect the realities of investigator operations rather than rigid sponsor models.
• Scalability and affordability, ensuring accessibility for academic, hospital-based, and independent research sites.
• Rapid deployment and ease of use, minimizing administrative overhead and staff training burden.
• Secure access controls and audit readiness, protecting sensitive participant information while enabling smooth remote monitoring and inspections.

The Cognidox system offers just this blend of flexible document management and robust, digital governance tools. It’s a highly flexible, fully validated document control system, that was built to support industries such as the medical device sector,

Right now, it’s providing investigator sites (like the NCCPG) with the tools they need to digitise, organise and control their essential clinical trial documentation — ensuring compliance, transparency, and complete operational efficiency.

By using Cognidox for your eISF, you can tailor the system to your site's needs, maintain full audit trails, streamline approvals and document updates, and stay fully inspection-ready — without the complexity or cost of traditional eTMF platforms.