Guest Blog Post – Author Nicole M. Palmer, MS

ClinEssentials is grateful to have Nicole Palmer, MS, an experienced Clinical Trial Administrator, Manager, and “Trial Master File (TMF) Enthusiast,” as a guest blogger. Nicole is the CEO of Granular Level, a Trial Master File Consulting company that takes care of all your Trial Master File career needs. Nicole’s impressive and extensive list of TMF specialties includes TMF metrics, reviews, plans, quality control, audits, the CDISC TMF Reference Model, and more.

We invited Nicole to write an informative piece about the Trial Master File and the important roles Clinical Trial Managers (CTMs), Clinical Research Associates (CRAs), and Clinical Research Coordinators (CRCs) play in maintaining it.

Thank you, Nicole, for the insight and information about the Trial Master File and the energetic passion you bring to the process.

Introduction

There is a misconception that only one department works in the Trial Master File (TMF). However, the TMF is a collaborative process built on the foundation of teamwork.

A Clinical Research Coordinator, Clinical Research Associate, and Clinical Trial Manager play vital roles in ensuring the TMF is inspection-ready to achieve compliance with the regulatory guidelines. First, let’s review the Trial Master File and Investigator Site File and why they are essential for every research study.

What is a Trial Master File (TMF)?

A Trial Master File is a collection of essential documents at the study level collected on the trial from all sources (Sponsor, CROs, Vendors, IRBs, and Sites) that help recreate a picture of the trial.

According to the International Council of Harmonisation’s (ICH) Good Clinical Practice (GCP) guidelines, “Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents demonstrate the compliance of the Investigator, Sponsor and Monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.”      

Every study must have a Trial Master File. Clinical Research has a golden rule: “If it’s not written down, it didn’t happen.” The Trial Master File must tell the whole clinical trial story and not leave out any details. It shouldn’t leave you guessing what happened or what didn’t happen.

There are three acceptable forms of TMFs: paper, electronic (eTMF), or hybrid, which consists of paper and electronic.

It is common to use the CDISC TMF Reference Model for the file structure. However, companies can use their own filing structure by clearly defining how documents will be classified and indexed. ICH GCP gives us a minimum list of essential documents to collect throughout a trial, but is not fully comprehensive.

Why is the TMF important?

A trial master file that is inspection-ready at all times and available for regulatory authorities will show:

✔ Compliance with the Protocol, Good Clinical Practice, and SOPs

✔ Protection of human subjects

✔ Successful management of a clinical trial

✔ Uncompromised data

What is an Investigator Site File (ISF)?

The Investigator Site File, sometimes referred to as the Regulatory Binder, is a collection of essential documents at the site level from the start of the trial through close-out. Each site must keep its own ISF.

Like the sponsor TMF, the ISF can be paper, electronic, or hybrid. Typically, all site documents are not in one binder but can be filed in multiple binders or in different locations. It is important to record where the essential documents are located at the site so they can be easily retrieved. The European Medicines Agency (EMA) discusses this in more detail here.

Documents you will find in an ISF include the following:

·   Protocol

·   Informed Consent Templates

·   Investigator Brochure

·   Protocol signature page

·   Investigator Brochure acknowledgment receipt

·   CVs of study teams

·   Copies of medical licenses (when applicable)

·   Proof of Good Clinical Practice training

·   IRB or EC approval letter along with IRB/EC approved documents

·   Delegation of authority log

The TMF Reference Model Excel spreadsheet provides a suggested list of what should be in your Sponsor TMF and your ISF by study type. Please refer to the image below.

What is the Clinical Trial Manager’s Role with the TMF?

A Clinical Trial Manager (CTM) is accountable and responsible for the overall completeness and management of the Trial Master File for their project. A CTM must maintain the integrity of the TMF and storage area. This includes developing, distributing, reviewing, and tracking essential documents.

According to the EMA, if a Contract Research Organization (CRO) manages the TMF, a CTM will oversee the responsibilities for the essential documents. CTMs work closely with the quality management department to ensure the TMF is inspection-ready. CTMs also help support TMF audits and/or inspections.

CTMs usually provide their company’s regulatory department with site-essential regulatory documents for submission to the FDA and other regulatory agencies. CTMs also contribute to updating SOPs related to the TMF. In addition, CTMs develop study plans that involve TMF activities and periodic oversight to remain compliant throughout the trial.

What is the Clinical Research Associate’s role with the TMF?

Clinical Research Associates (CRAs) are the primary contact points in a clinical trial and play a huge part in managing the sponsor TMF and the ISF.

The CRA does periodic reviews to ensure the TMF is complete and accurate. An eTMF platform can easily streamline this process by showing the expected, expired, or missing documents to the CRA. A paper TMF can be time-consuming and increases your chance of human error caused by manually entering TMF data into an Excel spreadsheet.

CRAs need to manage time efficiently when on site. Often, a site will only allow access to their ISF for a certain amount of time. CRAs must complete regulatory reviews within that time and document pending items in the monitoring report.

Here are a few time-saving tips to prepare CRAs to conduct a regulatory review during an upcoming monitoring visit. Prior to the CRA being on-site, it’s important to:

1. Review the last Interim Monitoring Visit report to see if any action items require follow-up.

2. If you are using an eTMF, it is imperative to run a report of all final files missing, expected, and expired documents. If you use a paper TMF, review the master checklist to see which documents you must collect while on site.

3. Before your visit, email the Clinical Research Coordinator (sometimes called the Study Coordinator) and let them know when you will be on-site and which documents you need.

By giving the CRC advanced notice of the documents needed, they can have them ready. If the site allows, they can send them electronically or provide remote access to the electronic ISF.

What is the Clinical Research Coordinator’s role with the TMF?

A Clinical Research Coordinator (CRC) plays a valuable role in maintaining or collaborating to maintain the Investigator Site File by being compliant with ICH GCP, FDA guidelines, and local regulatory requirements.

CRCs are responsible for maintaining research records of study activities, such as case report forms, IP records, the delegation of authority log, enrollment logs, patient registration, key personnel training, etc.

CRCs work with CRAs during monitoring visits to provide missing documents required for the TMF, are available for site audits, and address any findings promptly.

Conclusion:

Having well-defined roles and responsibilities by qualified and experienced individuals will ensure your Trial Master File is inspection-ready. Building a team and cultivating relationships is critical to collecting essential documentation.

Babe Ruth said it best: “The way a team plays as a whole determines its success. You may have the greatest bunch of individual stars in the world, but if they don’t play together, the club won’t be worth a dime.” The same holds true for the people who work in the TMF.

If you have any questions about TMF or want to connect with Nicole, email her here.