Trials Documents : The Essentials

Getting Organised

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The proper conduct of a clinical investigation can be complex. With various protocols, risk assessments, participant information sheets, contracts and financial agreements it can be a little overwhelming - especially when documents are revised, version-controlled, approved, redacted and more.

According to the internationally recognised guidelines for Good Clinical Practice (ICH-GCP E6(R2)) approved for use by the Food and Drugs Administration (FDA), European Medicines Agency (EMA) and the Medical Health Regulatory Authority (MHRA), "essential documents" are those which “individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced”.

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ICH-GCP E6(R2) identifies a minimum list of essential documents (where applicable for your study type). The functions and roles of these documents come into play at various stages of the trial:

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1. Before the clinical phase of the trial commences
2. During the clinical conduct of the trial
3. After completion and termination of the trial

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Though these definitions speak contextually to clinical audiences working on clinical trials of investigational medicinal products (CTIMPs), best practice suggests that a similar approach should be taken in non-CTIMP research. Since the nature of a clinical investigation might differ, where relevant, some of these files can be omitted from the trial as described in the ICH-GCP E6(R2) 8.1 addendum:

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“Essential documents for the trial should be supplemented or may be reduced where justified (in advance of trial initiation) based on the importance and relevance of the specific documents to the trial.”

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Keeping on top of your essential documents not only ensures that you are compliant with any regulatory and governance authority (FDA / EMA / MHRA). The level of filing of these documents at the investigator or institution and sponsor sites can also greatly assist in the successful management of a trial.

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Always remember that, in the event that an audit is required, whether this is internal or external, all of these essential documents can and should be provided in a human readable format.  

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[Stage 1] : Before the Clinical Phase of the Trial Commences

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A list of applicable documents in this stage which might be relevant:

• Investigator's Brochure (IB)
• Signed Protocol
• Sample CRF/eCRF
• Participant Information Sheet (PIS)
• Informed Consent Form (ICF)
• Other written information
• Financial aspects of the trial
• Insurance statement/s
• Signed agreements between all parties
• REC/IEC/IRB board approval
• REC/IEC/IRB board composition
• Regulatory authority authorization
• Normal value range lists for any tests to be carried out as per the protocol
• Accreditation / Certification / Validation documentation for any procedures or tests
• Samples of labels for products
• Instructions for handling Investigational Products (IP)
• Shipping records for trial-related materials.
• Certificate of Analysis (COA) of the Investigational Product
• Decoding procedures for blinded trials
• Master randomization list
• Pre-trial monitoring report
• Trial initiation monitoring report

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Stage 1, Section Overview:

The purpose of these documents is to ensure that the setup of the trial has been given due diligence, and that all aspects of proper conduct, finances and risks (whether data, participant safety or other) have been considered sufficiently. Moreover, oversight and documented approval by an independent ethics committee (IEC), research ethics committee (REC) or institutional review board (IRB) provides additional assurances that the trial can be safely green-lit.

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[Stage 2] : During the Clinical Conduct of the Trial

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In addition to documents in the first section (including any amendments, revisions and updates) relevant documents in this stage include:

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• Curriculum Vitae (C.V.) for the investigator/sub-investigators
• Monitoring Visit Reports (MVR)
• Signed Informed Consent Forms (ICF), or eConsent forms
• Source documents (source and/or eSource where appropriate)
• Signed, dated and completed case report forms (CRF or eCRF)
• Documentation of any CRF/eCRF corrections
• Notification of any serious adverse events related to reports
• Notification by the sponsor and/or investigator where applicable to regulatory authorities or IRB/IEC/REC of unexpected serious adverse reactions and other safety information
• Notification by the sponsors to investigators of safety information
• Interim or annual reports to any regulatory authorities and REC/IEC/IRB where appropriate
• Subject screening log/s
• Subject identification code list
• Subject enrolment log
• Investigational products accountability at the site
• Signature sheets (for users permitted to fill in eCRF during the trial)
• Records of any retained body fluids or tissue samples

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Stage 2, Section Overview:

During this stage, your study will be up-and-running, and you might find that your team are really familiar with documentation, updates, logs, amendments etc. This should flow fairly smoothly. If it doesn't, do not despair. You should have provisioned for any disasters before this and can surely pick up any loose pieces if things have not gone 100% according to plan. Remember, always consider whether you need to communicate any bumps in the road to sponsors, regulators or your REC/IEC/IRB.

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[Stage 3] : After Completion of Termination of the Trial

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After conclusion of the trial, you should already have most of your essential documents covered off and completed. In addition to the previous documents, you can expect (where applicable) to have the following documents completed at close:

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• Documentation of investigational product destruction
• Completed subject identification code list
• Audit certificate
• Final trial close-out monitoring report
• Treatment allocation and decoding documentation
• Final report by investigator to the IRB/IEC/REC and to any relevant regulatory authorities
• Clinical Study Report

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Stage 3, Section Overview:

After trial close-out - whether it was terminated or completed - new documents will come into play. The purpose of these documents is to prove that any intervention (e.g. IMP or other) was used according to the protocol, and to document any product that was not used or dispensed. Any unused product is typically destroyed and documentation to indicate this process has been completed is required on close-out. Interventions which have potentially life- or health-altering properties will need to be disposed of so that they do not pose a risk to others, animals or to the environment. In the event that participants are required to be de-anonymised, for example, if a follow-up of healthcare review is required, this must also be documented.

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Essential Documents : Where do I start?

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Using the guidelines of ICH-GCP E6(R2), and identifying these separate three stages of trial conduct, you should be able to quickly identify what might or might not be relevant for your trial.

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Ask yourself questions! ...

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... In order to assess...

• What is the nature of the intervention?
• Who will provide it and how will it be prepared?
• How many sites might be involved in this work?
• How long will the study be?
• Will there be any off-site work? E.g. Patient Reported Outcomes (PRO/ePRO)
• What systems will be used to support correct storage of the trial documents?
• What systems will be used to support correct data capture and data collection? Is a contract required with a vendor for this?
• Who will be involved in the trial altogether? E.g. Sponsors, sites, principal investigators (PIs), Clinical Research Co-ordinators (CRCs) or Associates (CRAs). How often will these people need to meet?
• What are the roles of specific personnel in the trail?
• The list goes on…

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If you are using a Contract Research Organization (CRO), they will likely have a lot of experience in this area and can often take on the brunt of these responsibilities for you (most likely at a cost).

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However you conduct your trials and whatever organizations, vendors, or systems you work with, keeping your documents together and organised will make things run much more smoothly.