clinical research &GCP (How to…set up a Trial Master File)

There are two principles of ICH GCP that are relevant to the essential documents required in the Trial Master File as follows:

All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification (ICH GCP 2.10).

The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s) (ICH GCP 2.10).

ICH GCP 8.1 also states that Trial master files should be established at the beginning of the trial, both at the investigator/institution’s site and at the sponsor’s office.

The essential documents are usually created by the sponsor or someone to whom the task has been delegated. The sponsor is responsible for having Quality Assurance and Quality Controls with written SOPs to ensure that the documents accurately record what happened during the trial

Before the trial starts, the sponsor/monitor is responsible for ensuring that the investigator has all the essential documents and will determine that they are being maintained during the study. The sponsor is also responsible for retaining all essential documents for the trial in conformance with the appropriate regulatory requirements.

The investigator should be informed by the sponsor that the essential documents need to be retained and should also be informed when they can be destroyed.

As already mentioned, the investigator should maintain the essential documents and take measures to avoid accidental or premature destruction of these documents

What type of trial are you setting up?

It is important to know what type of trial you are setting up. Is it a Clinical Trial with Investigational Medicinal Product (CTIMP)? If the answer is yes then you must use section 8 of ICH GCP and ensure that you comply with the relevant requirements.   For example, article 5 of the EU GCP directive combines the ICH GCP principles and states

All clinical trial information shall be recorded, handled, and stored in such a way that it can be accurately reported, interpreted and verified, while the confidentiality of records of the trial subjects remains protected.

Article 15.5 of the EU Clinical Trials Directive states that there will be detailed guidelines on the TMF and archiving published. Chapter 4 of the GCP Directive is about the essential documents, the TMF and archiving and there is also further guidance – ‘Recommendations on TMF & Archiving which can be found in Eudralex Vol.10 chapter 5.

Standard Operating Procedures (SOPs)

Your company/organisation should have SOPs for Setting up Trials and TMF. These should be practical and easy to follow. However, it is important to define at the start exactly who is responsible for what within the company/ organisation. Is it all to be done by one person (CRA) or can the tasks be shared between CRA, CT Assistant and secretary? The tasks could be broken down into:

• Who creates which documents?
• Who sets up the Trial Master File?
• Who does the filing and checking that the files are being maintained correctly?
• Who is responsible for the final check before archiving?
• Who is the archivist?

Quality and Version Control

Paper documents should be created by a reasonable quality printer on good quality paper asthey have to remain complete and legible condition for many years (GCP Directive Article 20). They should have headers with at least the short title/protocol number on each page and identify the document and sponsor. The footers need to have the version number, date created and page number X of Y as a minimum. Some people like to use draft and final with the version numbers and some may add the file name.

It is important that you organise your computer into folders so that you know where the electronic versions are and others could find the document if they needed to.

Some companies will use binders and others will use suspension files for the documents but regardless of what system is used, start your file as soon as you have the first document. Time spent in organising files will save time during the trial and prevents audit/inspection panic.

Study, Centre, Investigator Site Files and Pharmacy Files

In a multi centre trial, the TMF held by the sponsor will consist of a Study File and Centre Specific Files. Investigator Site Files and Pharmacy Files (if applicable) will be sent to each Investigator. Hopefully your SOP will have an index that you can use for each file. Obviously, in a single centre trial the Study File and Centre File will be the same. Each file should have a general correspondence section for correspondence that does not relate to other sections.

Study File (General File)

This file consists of the documentation relevant to the whole trial. Examples of the documents are the Regulatory (CTA) and Ethical Approvals, Protocol & amendments, Case Report Form (CRF), Patient Information Sheet (PIS) & consent form, Investigator Brochure (IB) & other information relating to the IMP, Safety Information & SAE reporting, Financial & other Agreements, Information relating to the Laboratory, Investigator list & training, Monitoring Guidelines & other Guidelines, and Study Reports.

In a multi country trial, there may also be country specific files containing information specific to each country.

Centre File

This file consists of the documentation specific to the centre or Investigator site. Examples of the documents are any centre specific or local Approvals, PIS & consent form, SAE reporting, Financial & other Agreements, Information relating to the site, pharmacy and laboratory, Investigator & training, and Monitoring reports.

Investigator Site Files

This file consists of all the documentation the Investigator needs to conduct the trial and will be provided by the sponsor at the beginning of the trial. Examples of the documents are the Regulatory (CTA) and Ethical Approvals, local Approvals, Protocol & amendments, CRF, PIS & consent form, IB & other information relating to the IMP, Safety Information & SAE reporting, Financial & other Agreements, Information relating to the investigator, site staff, laboratory, & pharmacy, Monitoring guidelines & other guidelines, Monitoring information and study reports.

Pharmacy Site File

It is good practice to provide the Pharmacy with a file that contains the information they need to dispense the IMP. Examples of the documents are the Regulatory (CTA) and Ethical Approvals, local Approvals, Protocol & amendments, IB & other information relating to the IMP, Drug Accountability forms, Pharmacy Agreement, Monitoring information and study reports.

File Note / Note to File

File notes/notes to file are useful tools to demonstrate that protocol deviations, safety issues, dispensing mistakes have been noticed and action taken. They are very useful for auditors and inspectors but care should be taken not to over use them.

They should be numbered and identify the study, investigator, and nature of the problem. They should be signed and dated by the CRA, the investigator if it relates to the site and the pharmacist if appropriate.

They should identify the problem and the action(s) taken to resolve it or prevent it happening again.