Archiving Essential Records under ICH E6(R3)

Part of Good Clinical Practice (GCP) — ICH E6(R3): Clinical Trial Closure and Archiving.

About 10 minutes. Free, in your language, no account needed.

Why this matters

Many sites still ask "which documents do we have to keep?" That is the wrong question now. ICH E6(R3), the current revision of the Good Clinical Practice (GCP) guideline, keeps essential records, and records include data and the relevant metadata. An audit trail is a record. A validation record is a record. A site that archives a tidy paper binder and lets the electronic audit trail expire has not archived the trial.

The word changed, and so did the scope

Under the previous revision, R2, section 8 was titled "Essential Documents". R3 changed the term to essential records.

The R3 Glossary defines essential records as "the documents and data (and relevant metadata), in any format, associated with a clinical trial that facilitate the ongoing management of the trial and collectively allow the evaluation of the methods used, the factors affecting a trial and the actions taken during the trial conduct to determine the reliability of the trial results produced and the verification that the trial was conducted in accordance with GCP and applicable regulatory requirements".

Three parts of that definition matter:

• Documents and data. Data are in scope, not only paperwork.
• And relevant metadata. Metadata is "the contextual information required to understand a given data element". Audit trails are metadata.
• In any format. The guideline is media neutral. Paper and electronic are treated the same.

Appendix C sets out the detail. It has three parts: C.1 Introduction, C.2 Management of Essential Records, and C.3 Essentiality of Trial Records, which carries the Essential Records Table.

Risk-proportionate: not every listed record exists

C.1.1 states that "The nature and extent of those records generated and maintained are dependent on the trial design, its conduct, application of risk proportionate approaches and the importance and relevance of that record to the trial."

C.3.3 makes the consequence explicit. For some trial records listed in the Essential Records Table, "their presence and nature are dependent on the trial design, trial conduct and risk proportionate management of the trial and may not be produced."

So a gap in the table is not automatically a finding. If a low-risk trial never produced a particular record, it is not missing. It never existed. What the site must be able to explain is why.

The Essential Records Table itself is framed conditionally: if these trial records are produced, they are considered essential and should be retained. An asterisk in the table marks records that should generally be in place before the trial starts.

C.3.1 lists the criteria for deciding whether a record is essential. Note its own caveat: "Such assessment, while important, is not required to be documented." A structured content list for the storage repository may be used to identify essential records prospectively. That is the practical route: agree the content list up front rather than assessing each record one by one at the end.

TMF and ISF are names, not requirements

This surprises experienced staff. C.2.3 says:

"These essential records should be maintained in or referred to from repositories held by the sponsor and by the investigator/institution for their respective records. These repositories may be referred to as a trial master file (TMF). The repository held by the investigator/institution may also be referred to as the investigator site file (ISF)."

Read the verb: "may be referred to". The requirement is that repositories exist and hold or point to the essential records. TMF and ISF are the names the industry gives them. Under R3 the primary term is essential records.

C.2.3 also allows records to be "referred to from" a repository. A record can live in its source system as long as the repository points to it reliably.

Managing the archive

Section 2.12.11 states the site's own duty in one sentence: maintain the trial records specified in Appendix C and required by the applicable regulatory requirements, and have control of all essential records generated by the investigator or institution before and during the trial. Control is the operative word. A record the site generated but cannot produce, because it sits in a system somebody else administers and switches off, was never under the site's control.

Appendix C then sets the operating rules.

• C.2.1 — records should be identifiable and version controlled where appropriate, and should include authors, reviewers and approvers as appropriate, with date and signature, physical or electronic, where necessary.
• C.2.4 — the sponsor and the investigator or institution should maintain a record of where essential records are located, including source records. Storage systems used during the trial and for archiving, whatever the media, should provide for appropriate identification, version history, search and retrieval.
• C.2.6 — records should be retained so they remain complete, readable and readily available, and directly accessible on request by regulatory authorities, monitors and auditors. "Alteration to the essential records should be traceable."
• C.2.7 — each party retains the essential records needed to fulfill its responsibility, and "The original records should generally be retained by the responsible party who generated them."
• C.2.9 — when a copy permanently replaces the original essential record, the copy should meet the requirements for a certified copy. A certified copy is one verified, by a dated signature or by generation through a validated process, to hold the same information as the original, including relevant metadata where applicable. So you may scan and discard the paper only if the scan is a certified copy.
• C.2.12 — some essential records are not trial-specific. They may relate to the investigational product, facilities, or processes and systems used across several trials, and may be retained outside the trial-specific repositories. The examples given are the Investigator's Brochure, master services agreements, standard operating procedures and validation records.

C.2.10 adds that some records are held only by the sponsor, some only by the investigator or institution, and some by both. C.2.11 requires care when sharing records where blinding or data protection legislation applies.

How long? E6(R3) gives no number

This is the correction that matters most, because the wrong answer is widely taught.

ICH E6(R3) does not state a retention period in years.

Section 3.16.3(a) says the sponsor, or a subsequent owner of the data, should retain the sponsor-specific essential records "in accordance with the applicable regulatory requirement(s)". The period comes from the law that applies to your trial, not from ICH.

Section 3.16.3(b) then places a clear duty on the sponsor. The sponsor should inform the investigators, institutions and, where appropriate, service providers in writing of the requirements for retaining essential records. The sponsor should also notify them in writing when the trial-related records are no longer needed, in accordance with applicable regulatory requirements.

Section 2.12.12 states the site side: the investigator or institution should retain the essential records for the required retention period in accordance with applicable regulatory requirements, or until the sponsor informs them that the records are no longer needed, whichever is the longest. They should also take measures to ensure availability, accessibility and readability, and to prevent unauthorized access and accidental or premature destruction.

Section 2.12.13 requires the investigator or institution to keep the sponsor informed of the name of the person responsible for maintaining the essential records during the retention period.

Section 3.16.3(c) requires the sponsor to report any transfer of ownership of the essential records to the appropriate authority as required, and to inform the investigator if sponsorship changes.

Retention durations do differ between regions and are set by national or regional law. Do not quote a number from another trial, another region or an older course. Read the written instruction the sponsor gave you for this trial.

In practice

Dr. Sarah's hypertension trial closes. Amina, her coordinator, opens the archive checklist and hits four questions.

"Do we still need the paper consent forms after scanning?" Only if the scans are certified copies under C.2.9. The site's electronic system generates scans through a validated process, so the copies qualify. Amina confirms this in writing with the sponsor before anything is discarded.

"The Essential Records Table lists an independent data monitoring committee charter. We do not have one." The trial had no such committee. Under C.3.3 that record was never produced. Amina notes the reason in the repository content list.

"How long do we keep everything?" Amina finds the sponsor's written retention instruction from section 3.16.3(b) in the site file. She does not use the figure a colleague remembers from a different trial. She files the instruction where the archivist will find it in ten years.

"Who owns the archive after I leave?" Under section 2.12.13, the site must tell the sponsor who is responsible for maintaining the essential records during the retention period. Amina names the institution's research records manager and notifies the sponsor in writing.

She also does one thing that is easy to forget. The electronic data capture system holds the audit trails. Those are relevant metadata and therefore part of the essential records. She confirms with the sponsor how they will remain retrievable and readable for the full retention period, and where the record of that arrangement is kept.

If you cannot retrieve it and read it, you have not retained it.

Key takeaways

• ICH E6(R3) uses the term essential records, not the R2 term essential documents, and the R3 definition includes documents, data and relevant metadata, in any format.
• Section 2.12.11 requires the investigator or institution to maintain the trial records specified in Appendix C and to have control of all essential records they generate before and during the trial.
• Appendix C.1.1 and C.3.3 make the essential records risk-proportionate, so some records listed in the Essential Records Table may simply not be produced for a given trial.
• Appendix C.2.3 says the repositories holding essential records may be referred to as a trial master file, and the investigator or institution repository may also be called an investigator site file; these are names, not the guideline's primary term.
• Appendix C.2.6 requires essential records to remain complete, readable and readily available, directly accessible on request, with any alteration traceable.
• Appendix C.2.9 allows a copy to permanently replace an original essential record only if the copy meets the requirements for a certified copy.
• Appendix C.2.12 allows non-trial-specific essential records, such as the Investigator's Brochure, master services agreements, standard operating procedures and validation records, to be retained outside the trial-specific repositories.
• ICH E6(R3) states no retention period in years; section 3.16.3(a) defers to applicable regulatory requirements and section 3.16.3(b) requires the sponsor to tell the site in writing what the requirement is and when records are no longer needed.