The Trial Master File (TMF) is crucial to maintain transparency, accuracy, and regulatory compliance in clinical trials. It contains all the essential documents for a clinical trial related to regulatory requirements as well as trial conduct. This article will provide a comprehensive overview of the TMF and its function.
First, it’s important to go over the common terms and their acronyms as the world of clinical research has its own vocabulary.
Clinical Trials: Common Terms
Sponsor: Initiates and manages the conduct of a trial. A trial sponsor can be a pharmaceutical company, university, government, or even an individual.
Investigator: The person responsible for the conduct of the clinical trial.
- Principal investigator (PI): The primary individual responsible for the conduct of a clinical trial. Also sometimes referred to as a chief investigator.
- Sub-investigator (Sub-I): One or more secondary individuals that are involved in a clinical trial but do not hold primary responsibility for its conduct.
Contract research organisations (CROs): Often act as the intermediary between the sponsor and the sites for trial management.
Clinical trial stakeholders: Anyone with a vested interest in the conduct of the trial. This includes but is not limited to the sponsor, investigator, patients, regulatory agencies, ethics committees, etc.
Site: A location where trial activities are carried out. In a clinical study there are usually multiple sites.
Trial master file (TMF): All essential documents relating to a clinical trial. There is typically a sponsor TMF and investigator TMF. The basic trial master file structure is the same for sponsors and investigators, but the specific documentation required can vary slightly and will be elaborated on below.
Investigator site file (ISF): The TMF that is maintained by the investigator. It is often referred to as TMF rather than ISF, but they are the same thing when referring to the investigator’s documentation.
Electronic trial master file (eTMF): The same as the paper TMF except the trial master files are stored via computer systems.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH): This organization serves to provide guidance for good clinical practice (GCP).
Good clinical practice (GCP): Provides ethical and scientific standards for human subjects research. It’s often referred to as GCP or ICH GCP interchangeably.
Institutional review board (IRB/WIRB): Reviews proposed clinical studies to ensure they meet regulatory guidelines. An IRB is a local review board, whereas the WIRB is a centrally located review board that is often used by trial sponsors.
Investigator’s brochure (IB): All data regarding an investigational medicinal product, both clinical and non-clinical.
Source documents: The original documents, or documentation, of a clinical trial subject’s data.
Case report form (CRF): Forms used to collect data from or about study subjects. They might be questionnaires given to subjects or forms used by the trial team to document pertinent information.
Electronic case report form (eCRF): The same as a CRF except electronic.
Electronic data capture (EDC): An electronic system used to record clinical trial data via eCRFs. Often paper CRFs are used to collect data and then said data is later entered into an EDC.
Interactive response technologies (IRT): Electronic systems that can aid in several aspects of a clinical trial. They are primarily known for being used to randomize patients and ensure the study treatment remains blinded.
Investigational medicinal product (IMP): Per the European Union, an IMP is any investigational medicinal product being used in a clinical trial.
Auxiliary medicinal product (AMP): Any medicinal product used in a clinical trial that does not serve as the investigational product itself.
Good manufacturing process (GMP): Process to ensure products are made according to a quality standard.
Investigational device exemption (IDE): An FDA application used for a medical device that’s required for full market approval.
Premarket approval (PMA): An FDA process to ensure a class III medical device meets the standards of regulatory agencies and scientific rigor.
Marketing authorisation application: An application required in the UK to get a medicine on the market.
Informed consent (ICF): Informed consent is the process of explaining the details of a clinical trial to a potential subject so they can make an informed decision on whether or not to participate in the trial. An ICF is the actual form used.
Study monitoring: A study monitor will review a site’s trial master file and its documents as well as all collected data. They ensure there is compliance with ICH guidelines and overall data integrity.
Trial Master File Structure
While the exact TMF structure will vary by trial, there is a level of documentation required in all of them. Regulatory requirements dictate this, and this is true whether the trials are industry-sponsored or investigator initiated studies. Certain documents, such as medical licenses, proof of GCP training, and documentation of study procedures are part of this minimum list.
Trial master file management is an ongoing process for the duration of the study, with the master file being updated as trial documentation is performed. These documents provide an audit trail of study activities and should be able to stand on their own without any additional explanation.
Without any additional explanation in this context simply means that the documentation stands on its own, with all relevant clinical and non-clinical data included to provide a clear, full picture of an event.
There are a set of minimum essential documents that need to be included in every trial master file to ensure compliance with regulatory authorities. Below is a list of these critical documents. Note that changes, amendments, corrections, and/or updates to these documents should also be included in the TMF.
Before and During the Clinical Trial
- Investigator brochure.
- Protocol, including any and all amendments with sample CRFs.
- Informed consent form and any accompanying documentation related to ensuring patients can give adequate consent.
- Financial agreement between sponsor and site.
- Statement on insurance for patient injury (if applicable).
- Any and all signed agreements between the site/investigator and sponsor, contract research organizations and sponsors, etc.
- All institutional review board approvals along with the documents included in said approval.
- Institutional review board document indicating they are GCP compliant.
- Any and all documents related to qualifications, such as CVs and medical licenses.
- Certificate or other document indicating qualification to perform medical or laboratory testing where applicable.
- Example label from investigational product (required for sponsor master file only).
- Instructions for handling all investigational products and any other trial products.
- All shipping records, where applicable.
- For investigational products, a certificate of analysis (only required in sponsor master file).
- Instructions for unblinding in the event it becomes necessary (while investigator master files maintain this, the sponsor might have to have this sourced by a third party if required).
- List of all randomizations (required only for sponsor master file, or third party file if necessary).
- Monitoring reports (only the sponsor trial master file has to include the report indicating site qualification for the trial and the general monitoring reports that accrue throughout the study. However, both the investigator and sponsor master files should include the trial initiation report that shows procedures for said trial were reviewed with the investigator and associated staff).
- Communication related to trial conduct, which can include letters, notes, emails, or summaries of phone calls. This helps provide an audit trail and prevent confusion down the line.
- Signed ICFs should be maintained in the investigator master file only as they can protected health information (PHI).
- Source documents should be included only in the investigator master file.
- CRFs, including any corrections to CRFs, that are signed and completed should be maintained by both the sponsor and investigator, with the sponsor master file holding the original and the investigator the copy.
- Notification from investigator of serious adverse events, including those reported to regulatory authorities.
- Notification from sponsor concerning safety information.
- Review board annual reports.
- Subject screening log should be maintained in the investigator master file, and only where required for sponsors. Note that anything identifying a patient would have to be de-identified before providing to a sponsor as they are not permitted to view protected patient privacy data.
- Subject identifiers should only be stored in the investigator master file.
- Enrollment log should only be maintained in investigator master file.
- Investigational product accountability.
- Signature sheet dictating all individuals who can complete and correct CRFs
- If any bodily fluids or tissue samples are kept it must be recorded in the trial master files.Final Documents at Conclusion of the Trial
- Documentation of investigational product’s destruction at end of trial. Only maintained in investigator master file if the site is responsible for product destruction.
- Documentation of final treatment arms and any deidentification that occurred in sponsor master file.
- Investigator’s final report to regulatory agencies if applicable.
- Clinical study report.
TMF Reference Model
Clearly there are a lot of documents listed as essential for a trial master file. Additionally, they have to be continually monitored and updated as applicable, making it a fairly formidable task. An all-too-common issue in clinical research is communication, or lack thereof, pertaining to the trial master file.
The Drug Information Association created a TMF reference model to help mitigate this issue and streamline TMF structure for investigators, sponsors, and CROs. Importantly, the TMF reference model combines the documents for both investigator and sponsor master files, so the TMF structure will have to be customized some to account for the necessary separation of some essential documents between sponsor and investigator.
Following the TMF reference model helps ensure GCP compliance is achieved and therefore readiness for regulatory inspections/monitoring visits as well. While the reference model certainly provides an excellent template for a general paper-based trial master file structure, more and more researchers are turning to an electronic trial master file for maintaining essential documents.
Electronic systems following the reference model are increasingly used for TMF management. The trial master file structure itself will be the same as it was on paper, with the ease of electronic storage. Many eTMFs allow users to archive and later access said archived data at will. System access can be granted to the appropriate parties on an as needed basis.
Data management becomes greatly simplified with interactive tools to quickly check on documents that need attention (or identify missing documents that should be uploaded) and ensure regulatory affairs are up to date. In other words, an online TMF reference model allows for constant electronic inspection readiness rather than having to review and file every paper document by hand.
Granted, not every TMF management service will have these interactive features; if not sponsors and investigators are still responsible for proper documentation so it’s important to know the capability of an eTMF management system.
As noted above, when the trial master file structure follows the TMF reference model and is incorporated into an eTMF, reviewing documentation becomes much easier for all involved parties from the sponsor to the site. It’s a way to collectively permit evaluation of the trial’s documentation.
Some eTMFs have automated reports, and this data produced provides insights on not only the TMF but even detailed reports on site performance.
On the sponsor side, data produced from various reports in an eTMF can illustrate which sites are the highest or lowest enrolling, understand the decision-making process of the most efficient versus most difficult site, etc. Naturally, the clinical operations from site to site will vary and this can impact how enrollment for trials is accomplished. Regardless, better understanding the trial process on an in-depth, per site basis helps elucidate problem areas and highlight what works well.