Essential records and the trial master file

A clinical trial's essential records are the documents and data that let its management be run and its conduct and the reliability of its results be evaluated. ICH E6(R3) sets which records count as essential, which party holds each and in what repository, what its table of them lists, and how long they are kept and who may see them.

What makes a record essential and who relies on it

Essential records are the documents and data, with their relevant metadata and in any format, associated with a clinical trial that facilitate its ongoing management. ¹ Together they allow evaluation of the methods used, the factors affecting the trial and the actions taken during its conduct, so that the reliability of the results can be determined and the trial can be verified as conducted in accordance with GCP and applicable regulatory requirements. ¹

Many records are generated before and during a trial, and their nature and extent depend on the trial design, its conduct, the application of risk-proportionate approaches, and the importance and relevance of each record to the trial. ² Which of them are essential is based on consideration of the guidance in the guideline's appendix on essential records. ²

Essential records permit and contribute to evaluating the conduct of a trial, both the investigator's and sponsor's compliance with GCP and applicable regulatory requirements and the reliability of the results produced. ² They are used as part of investigator oversight and sponsor oversight, including monitoring, and they are used by the sponsor's independent audit function and during inspections by regulatory authorities to assess the trial's conduct and the reliability of its results. ² Certain essential records may also be reviewed by the ethics committee in accordance with applicable regulatory requirements. ²

In an annual report of the Good Clinical Practice Inspectors' Working Group cited in 2024, issues with essential documents were the most common findings of European Medicines Agency inspectors, and 7.5% of those findings were graded critical and 59% major. ³ Under ICH E6(R2), the earlier version of the guideline, essential documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of good clinical practice and with all applicable regulatory requirements. ³ From this, practitioners writing in 2024 conclude that the investigator's brochure, the study protocol and the informed consent forms are always reviewed during quality assurance audits or regulatory agency inspections. ³

The trial master file and who holds each record

Essential records should be maintained in, or referred to from, repositories held by the sponsor and by the investigator or institution for their respective records. ⁴ These repositories may be referred to as a trial master file, and the one held by the investigator or institution may also be referred to as the investigator site file. ⁴

The sponsor and the investigator or institution should keep a record of where the essential records are located, source records included. ⁴ The storage systems used during the trial and for archiving, whatever the media, should provide for appropriate identification, version history, search and retrieval. ⁴ Records should be identifiable and, where appropriate, version controlled, and should include authors, reviewers and approvers as appropriate, along with date and signature, electronic or physical, where necessary. ⁴

The sponsor and the investigator or institution should ensure that essential records are collected and filed in a timely manner, which can greatly assist the successful management of a trial. ⁴ Some essential records should generally be in place before the trial starts and may be updated during it. ⁴ The records should be retained so that they remain complete, readable and readily available and are directly accessible on request by regulatory authorities, monitors and auditors, and any alteration to them should be traceable. ⁴

Each party should ensure the retention of the essential records it needs to fulfil its responsibility, and the original records should generally be retained by the party that generated them. ⁴ To fulfil their responsibilities in the conduct of the trial, each party may need access to, or copies of, the other's relevant essential records before and during the trial, and at the end of the trial each should retain its own. ⁴ A record's location may vary during the trial with its nature: for example, the investigator may access suspected unexpected serious adverse reaction reports through a sponsor-provided portal, and the investigator or institution would still need to retain those records at the end of the trial. ⁴ Some records are typically kept only by the sponsor, such as those relating solely to sponsor activities like data analysis, and some only by the investigator or institution, such as those containing confidential participant information; others may be retained by either or both. ⁴

Where the sponsor transfers activities to service providers, or the investigator or institution delegates them, arrangements should be made for accessing and managing the essential records throughout the trial and for retaining them after it. ⁴ Where a copy permanently replaces an original essential record, the copy should fulfil the requirements for certified copies. ⁴ A certified copy is a copy of the original record, in any media, that has been verified by a dated signature or by generation through a validated process to hold the same information as the original, including its relevant metadata where applicable. ⁵ Careful consideration should be given to sharing records where there are blinding considerations and where the records are subject to applicable data protection legislation. ⁴

Certain essential records may relate not to one trial but to the investigational product, facilities, or the processes and systems, computerised systems included, involved in running multiple trials, and these may be retained outside the trial-specific repositories. ⁴ Examples are the investigator's brochure, master services agreements, standard operating procedures and validation records. ⁴

The essentiality criteria

The assessment of whether a record is essential and has to be retained should take into account a set of criteria. ⁶ That assessment, while important, is not required to be documented, and a structured content list for the storage repositories may be used to identify essential records prospectively. ⁶

A record is essential if it is a document submitted to or issued by the regulatory authority or ethics committee, including related correspondence and documentation of regulatory decisions or approvals or favourable opinions; a trial-specific procedure or plan; relevant correspondence or documentation of meetings about important discussions or trial-related decisions concerning the conduct of the trial and the processes used; documentation of the conduct of relevant trial procedures, such as a database lock checklist produced by following data management standard operating procedures; documentation of the arrangements between parties and of insurance and indemnity arrangements; documentation of compliance with the requirements and any conditions of the regulatory authority's approval or the ethics committee's favourable opinion; or documentation of the composition and, where appropriate, the functions, correspondence and decisions of any committee involved in the trial's approval or conduct. ⁶

It is also essential if it demonstrates that a trial-specific computerised system is validated and that non-trial-specific systems such as clinical practice systems have been assessed as fit for purpose for their intended use; if it has been authorised or signed by the sponsor or investigator to confirm review or approval; or if it is, where necessary, documentation demonstrating the signatures or initials of staff undertaking significant trial-related activities such as completing data acquisition tools. ⁶

Four criteria concern consent and the qualifications of the people involved. A record is essential if it documents what information was provided to potential participants and that their informed consent was appropriately obtained and maintained; if it documents that sponsor personnel involved in the conduct, and individuals performing significant trial-related activities on their behalf, are qualified by education, training and experience; if it documents the same for the investigator and those delegated significant activities by the investigator, particularly where those activities are not part of their normal role; or if it documents that service providers are suitably qualified for the activities delegated or transferred to them. ⁶

Further criteria concern the data, the oversight and the analysis behind the results. A record is essential if it contains the data and the relevant metadata needed to allow appropriate evaluation of the conduct of the trial; if it relates to sponsor or investigator oversight of participant safety during the trial, including compliance with safety reporting requirements between sponsors and investigators, regulatory authorities and ethics committees, and informing participants of safety information as necessary; if it documents that laboratory activities and other tests used in the trial are fit for purpose; if it documents sponsor oversight of site selection and of monitoring and audit, where appropriate, and provides information on arising issues, noncompliance and deviations detected and on the corrective and preventive actions implemented; if it documents compliance with the protocol or with the procedures for managing and statistically analysing the data and producing any interim report and the final report; or if it documents the collection, chain of custody, processing, analysis and retention or destruction of biological samples. ⁶

Several criteria concern the investigational product: records providing relevant information on the product and its labelling; on its shipment, storage, packaging, dispensing, randomisation and blinding; where appropriate, traceability and accountability information from release by the manufacturer through dispensation and administration to participants, return and destruction or alternative disposition; and information on the identity and quality of the product used. ⁶ Documentation of the processes and activities relating to unblinding is essential in its own right. ⁶

The last three criteria concern the participants themselves: records documenting recruitment, pre-trial screening and the consenting process, and participants' identity and chronological enrolment as appropriate; records documenting the existence of the participants and substantiating the integrity of the data collected, which includes the source records related to the trial and to the participants' medical treatments and history; and records defining the processes and practices in place in the event of a security breach, in order to protect participants' rights, safety and well-being and the integrity of the data. ⁶

The Essential Records Table

Applying those criteria, the guideline lists the records considered essential in its Essential Records Table, and these should be retained when produced. ⁶ The table is not exhaustive, and the sponsor or the investigator may consider other trial records essential. ⁶ For some records in it, presence and nature depend on the trial design, its conduct and its risk-proportionate management, and they may not be produced. ⁶

Records that should generally be in place before the trial starts are marked "before start". ⁷

• The investigator's brochure or a basic product information brochure, such as a summary of product characteristics, package leaflet or labelling (before start)
• The signed protocol (before start) and subsequent amendments during the trial
• The dated, documented approval or favourable opinion of the ethics committee of the information provided to it (before start)
• The ethics committee's composition (before start)
• The regulatory authority's authorisation, approval or notification of the protocol (before start) and of subsequent amendments during the trial, where required
• Completed signed and dated informed consent forms
• The completed participant identification code list and enrolment log
• Notification by the originating investigator to the sponsor of serious adverse events and related reports, where required; notification by the sponsor or investigator, where required, to regulatory authorities and ethics committees of suspected unexpected serious adverse reactions and other safety information; and notification by the sponsor to investigators of safety information, where required
• Interim or annual reports to the ethics committee and regulatory authorities, where required
• Source records
• Data and relevant metadata, including documentation of data corrections, in the data acquisition tools
• The final report to the ethics committee and regulatory authorities, where required
• Interim, where applicable, and final clinical trial reports
• A sample of the data acquisition tools provided to the investigator or ethics committee, such as case report forms, diaries and clinical outcome assessments including patient-reported outcomes (before start)
• A sample of the information given to trial participants (before start): informed consent materials including all applicable translations, any other documented information such as instructions for use of an investigational product or a device, and the advertisement for participant recruitment
• The arrangement between parties on the financial aspects of the trial (before start)
• The insurance statement (before start)
• Signed agreements between the involved parties (before start), such as investigator or institution and sponsor, investigator or institution and service providers, sponsor and service providers, and sponsor and independent data monitoring committee or adjudication committee members
• Documentation of the selection, assessment (before start) and oversight of service providers conducting important trial-related activities
• Relevant documents evidencing the qualifications of the investigators and sub-investigators involved in conducting the trial, such as curricula vitae (before start)
• Trial-specific training records (before start)
• Documentation of the delegation of trial-related activities by the investigator (before start)
• A signature sheet documenting the signatures and initials of the investigator and individuals delegated by the investigator, unless only electronic signatures are used, which can be combined with the documentation of delegation (before start)
• Normal values or ranges for the medical, laboratory or technical procedures and tests included in the protocol (before start)
• Certification, accreditation or other documentation, including of validation where required, confirming the suitability of the medical, laboratory or technical procedures and tests used during the trial (before start)
• Documentation of the collection, processing and shipment of body fluid and tissue samples
• Documentation of the storage conditions of body fluid and tissue samples
• A record of body fluid and tissue samples retained at the end of the trial
• A sample of the labels attached to investigational product containers
• Instructions for handling the investigational product and trial-related materials, such as a pharmacy manual, if these are not included in the protocol or investigator's brochure (before start)
• Shipping records for the investigational product and trial-related materials (before start)
• Certificates of analysis of the investigational product shipped (before start)
• Investigational product accountability at the investigator site
• Documentation of investigational product storage conditions, including during shipment
• Records of relabelling of the investigational product at the investigator site
• Documentation of investigational product destruction or alternative disposition
• Emergency decoding procedures for blinded trials (before start)
• The master randomisation list (before start)
• Instructions for use of important trial-specific systems, such as an interactive response technology user manual or an electronic case report form manual (before start)
• Records demonstrating fitness for purpose, such as maintenance and calibration, for equipment used for important trial activities (before start)
• Treatment allocation and decoding documentation
• The completed participant screening log
• Site monitoring reports, including site selection (before start), initiation (before start), routine and close-out
• Centralised monitoring reports
• Records and reports of noncompliance, including protocol deviations and corrective and preventive actions
• Documentation of relevant communications and meetings
• The audit certificate
• Documentation relating to data finalisation for analysis, such as query resolutions, serious adverse event reconciliation, quality control reports, coding completion and output data sets
• Documentation of trial-specific computerised system validation, such as specifications, testing, the validation report and change control (before start)
• Documentation of the assessment of fitness for purpose of non-trial-specific computerised systems used in the trial, such as clinical practice computerised systems (before start)
• Documentation relating to the statistical considerations and analysis, such as sample size calculations (before start), analysis set decisions, analysis data sets, analysis programs, quality control records and outputs
• Trial-specific plans and procedures, such as the risk management, monitoring, safety, data management and data validation plans (each before start) and the statistical analysis plan
• Procedures (before start), meeting minutes and submissions to any independent data monitoring or adjudication committee

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Retention

The investigator or institution should have access to, the ability to maintain and control of all the essential records they generate before and during the trial. ^{2, 8} They should maintain the trial records as the essential records appendix and applicable regulatory requirements specify, and retain them for the period those requirements set or until the sponsor informs them the records are no longer needed, whichever is longer. ^{2, 8} They should take measures to ensure the records' availability, accessibility and readability and to prevent unauthorised access and accidental or premature destruction. ⁸ They should keep the sponsor informed of the name of the person responsible for maintaining the records during the retention period, for example when a site closes or an investigator leaves it. ⁸

The sponsor, or any subsequent owner of the data, should retain the sponsor-specific essential records in accordance with applicable regulatory requirements. ⁹ It should inform the investigators, institutions and, where appropriate, service providers in writing of the retention requirements, and notify them in writing when the trial-related records are no longer needed under applicable requirements. ⁹ It should report any transfer of ownership of the essential records to the appropriate authorities as required, and inform the investigator if the sponsorship of the trial changes. ⁹

Direct access

Direct access is permission to examine, analyse and verify records that are important to the evaluation of a clinical trial, and it may be performed on-site or remotely. ¹⁰ The sponsor should ensure that the protocol or another documented agreement specifies that the investigator or institution will provide direct access to source records for trial-related monitoring, audits, regulatory inspection and, in accordance with applicable requirements, ethics committee review. ¹¹ It should also ensure that participants have consented to direct access to source records for those purposes. ¹¹ On request from a monitor, auditor, ethics committee or regulatory authority, the investigator or institution should make all requested trial-related records available for direct access. ⁸

Any party with direct access, such as domestic and foreign regulatory authorities and the sponsor's monitors and auditors, should take reasonable precautions, within the constraints of applicable requirements, to maintain the confidentiality of participants' identities and their data and of the sponsor's proprietary information. ¹⁰