Master the TMF—a Clinical Trial Walkthrough

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Master the TMF—Clinical Trial Retraced

By definition, clinical trials involve human subjects (patients, healthy volunteers, or both) to test new medical devices, treatments, and procedures. All the documentation research companies collect before and during the trial makes up a Trial Master File.

These documents are necessary for the approval and conduct of clinical trials and their phases, and many countries have strict regulations governing which ones go into the TMF making.

Though the U.S. Food and Drug Administration (FDA) has rules and guidelines for documents that create a TMF, the organization does not specifically require research companies to prepare it. If another regulatory authority requires them to do so, those companies must oblige by following ICH’s GCP code during clinical trials.

In case you found a clinical trial you would like to participate in, this short introduction to TMFs gives you a better insight into some particulars.

What Is a Clinical Trial Master File?

A Trial Master File (TMF) is a collection of the essential and additional documents (superseded documents, correspondence, etc.) used to conduct and manage the trial. A well-compiled TMF demonstrates the sponsor’s and investigator’s compliance with the Good Clinical Practice (GCP) standards and applicable (local) regulatory requirements.

TMFs consist of two main parts:

  1. The sponsor-generated TMF
  2. The investigator-generated TMF, also known as investigator site file (ISF)

Certain TMF documents will belong to both parties, but others will be exclusive to the party that produced them. The sponsor and the investigator are responsible for the documents they generated and should have access to them anytime.

There are certain criteria that a TMF has to fulfill. It has to:

  • Contain the clinical trial essential documents at all time
  • Be sufficient to reconstruct all the steps taken during the trial
  • Enable the traceability of content alterations
  • Provide document identification, version history, search, and retrieval
  • Be readily available for audit upon request by any regulatory authority

Once the TMF has been compiled and authorized, the clinical trial can commence, and it officially ends when the monitor confirms that all documents are in the appropriate files.

What Are the Essential Documents?

Essential Documents are all the records, images, and reports that—individually or collectively—reflect the clinical trial steps and the data produced. They are subject to audit and inspection by the sponsor’s independent auditor and regulatory authorities charged to confirm compliance with the GCP guidelines, trial validity, and the collected data integrity.

As they assist with trial management, the Essential Documents are of huge significance to the sponsor, monitor, and investigator. Depending on the stage of the trial during which the documents are produced, they branch into three groups:

  1. Pre-trial documents
  2. Trial documents
  3. Post-trial documents

Each document contains the description of the purpose and the filing repository (sponsor TMF, investigator TMF, or both).

You can find some of the Essential Documents contained in each group in the table below:

Essential Documents GroupDocument Example

Pre-trial documents

  • Signed protocol
  • Informed Consent Form
  • Investigator’s Brochure

Trial documents

(Added to the file as they become available)

  • Investigator’s Brochure updates
  • Revisions to the protocol, informed consent form, and other written information given to the trial participants
  • Regulatory authorities’ approvals

Post-trial documents

(Added to the file upon the trial completion)

  • Final close-out
  • Clinical Study Report
  • Investigational product’s accountability at site

You can find the full list of the essential documents in Section 8 of the ICH E6 (R2): Guideline for good clinical practice.

Depending on the nature of the research, the document reduction will be possible, but the justification for it should be in the TMF. Reversely, if a trial requires document supplementation, it should be included in the TMF.

What Does Informed Consent Mean?

According to FDA's Informed Consent: Draft Guidance for IRBs, Clinical Investigators, and Sponsors, informed consent is a process of appraising (prospective) subjects of all the details related to the clinical investigation.

The process enables subjects to understand trial participation implications. It also allows them to inquire about the clinical trial to be able to make an informed decision. Title 21 of the Code of Federal Regulations 50.20. stipulates that under no circumstances can investigators or other research staff use coercive of exculpatory language.

The process also involves reviewing, discussing, and signing the contents of the Informed Consent Form.

Informed consent is an ongoing process continuing throughout the clinical trial, which means the subject can request additional information throughout the trial.

The following points make up the basic elements of informed consent. They are:

  • The trial description
  • Risks and discomforts
  • Benefits
  • Alternative treatments or procedures
  • Confidentiality
  • Compensation and medical care in the event of injury
  • Voluntary participation
  • Contacts

Note: voluntary participation implies that the subject may refuse to participate or withdraw from the trial anytime without penalty.

Do TMFs Protect Subject Privacy?

Yes, they do. Only the investigator TMFs can contain documents with subjects' data. If the investigator shares those documents with the sponsor/CRO, the subject names should be listed under pseudonyms.

How Are TMFs for Clinical Trials Stored?

TMFs can be paper, electronic, or hybrid (both paper and electronic). Regardless of the media used, TMFs (including eTMFs) have to be stored in highly-secured facilities with measures in place to protect all documentation from damage and loss.

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